Polymeric Nanoplatforms for the Targeted Treatment of Prostate Cancer

Abstract

Traditional drug formulations are facing issues of toxicity to normal cells, stability, and bioavailability, calling for suitable nanocarriers such as polymeric nanoparticles for targeting prostate cancer. This chapter reviews the basics of polymeric nanoparticles and targeted treatment of prostate cancer. We detail targeting strategies and types of polymeric nanoparticles.

16.1 Introduction

Cancer is one of the world's principal public health problems (Fitzmaurice et al. 2015; Padhi and Behera 2020). It is the second-largest consequence of patient deaths and is accountable for seven million deaths annually (12.5% worldwide) (Orive et al. 2005; Siege et al. 2014). Followed by cardiovascular disease, cancer in the United States is the second most frequent cause of death with a total of 1,665,540 new cancer cases and 585,720 deaths in 2014 (Siege et al. 2014). More particularly, as per american cancer statistics evidence (2014), prostate cancer (233,000), female breast cancer (235,030), lungs/bronchus cancer (224,210), colon/rectum cancer (136,830) seems to be the most common forms of cancer (Salaam et al. 2018; Siege et al. 2014). By 2040, there will be an increase of 29.5 million new cancer cases a year, with 16.4 million cancer-related deaths. Worthy to mention that, about 43% of all cancers diagnosed in men in 2020 are prostate cancer, lung cancer, and colorectal cancer (Oh et al. 2019).

Prostate cancer is the common non-skin (Chhabra et al. 2018), the male reproductive system-associated cancer type that develops in the prostate gland. Additionally, it is the most frequent malignancy in men and accounts for 10% of the new estimated cases of cancer (Rawla 2019; Siege et al. 2014). In the United States (2020), prostate cancer accounted for 191,930 new cases and 33,330 (5.5%) death cases (Oh et al. 2019). As per the published report, the world's second most common male malignancy is prostate cancer, with 1,276,106 new diagnoses and 358,989 deaths (3.8% of all men cancer deaths) in 2018 (Rawla 2019). Although an estimated 2,293,818 new cases are to be reported by 2040, the mortality rate is small (1.05% increase) (Rawla 2019). It is well known that prostate cancer may be reasonably harmless or highly aggressive. In the case of aggressive prostate cancer, it soon spreads to lymph nodes and bone in particular. Furthermore, prostate cancer is categorized and further staged for aggressiveness and the exact extent to which it spreads. Herein, stages A and B are restricted to the prostate gland, whereas, stage C is outside the gland, but locally only, and stage D is expanded into lymph nodes and distant sites (Ast 2003).

Prostate cancer pathogenesis has relied heavily on androgen receptor signaling, a ligand-dependent transcription factor (Chhabra et al. 2018). In general, prostate cancer is again largely considered an old-age (average age 66 years) disease because of the more frequent occurrence in older individuals (Rawla 2019; Siege et al. 2014). Prostate cancer may also be associated with age, as it influences 80% of males over 80 years. Based on the age group, the percent of new cases of prostate cancer have been depicted in Fig. 16.1. Prostate cancer risk also includes inheritance, race, alcohol intake, obesity, sexual behavior, ultraviolet radiation exposure, diet, gender, inflammatory diseases, etc. (Chiam et al. 2014). It should be noticed that the prostate cancer prevalence of african-american men in contrast with white men is higher (Panigrahi et al. 2019). The explanations for this imbalance are believed to be social, environmental, and genetic variations (Rawla 2019).

Fig. 16.1

Prostate cancer percent new cases by age group from 2013–2017 (all races of male population). The figure represents the percentage of male patients suffering from prostate cancer and classified according to age group

Prostate cancer diagnosis and treatment were linked to depressing moral systems, nervousness, psychological distress, and reduced well-being efficiency (Mohamed et al. 2012), often linked to physical symptoms viz. erectile dysfunction, fecal leakage diseases, and pathetic urinary stream (Johansson et al. 2009). The conventional treatment methods for prostate cancer are surgery (i.e. resection of tumors), chemotherapy, and radiation therapy (Nilsson et al. 2004). Notably, this technique can be used alone or in combination to produce realistically positive outcomes. One of the best ways to cure metastatic diseases (known as cancer) is to undergo chemotherapy using antimetabolites or alkylating agents (Salaam et al. 2018). Regardless of the impressive advantages of chemotherapy, remarkable toxicity, reduced drug intake, overtime tolerance to drugs in the cancer cells and minimal patient-specific therapies are some of the foremost chemotherapy concerns. Unfortunately, toxicity is a factual concern, because chemotherapy will target cells without specificity that divide hurriedly and annihilate perfectly healthy, non-cancerous cells (hair and immune cells) of the human body (Schirrmacher 2019). Consequently, researchers spotlight mostly on tailored delivery mechanisms, with selectively terminating cancer cells and creating mostly patient-specific treatment regimes.

In this book chapter, the fundaments of revolutionary polymeric nanoparticles and their ground-breaking applications to prostate cancer have been elaborated in detail. Furthermore, it gives a comprehensive insight into targeting strategies and types of polymeric nanoparticles that have been reported to prostate cancer treatment. It discussed the recent advances in polymeric nanoparticles and the application section of these polymeric nanoparticles. Notwithstanding this, current challenges and future-outlook of polymeric nanoparticles for prostate cancer therapy have also been discussed in brief. Overall, this chapter gives detailed insight into the pathway and type of polymeric nanoparticles for prostate cancer treatment, which may persuade their future applications in biomedical fields.

Nanotechnology has a huge perspective for revolutionizing precise detection and efficient treatment of cancer (Padhi et al. 2018). Over the recent four decades, comprehensive work has been performed in the field of prostate cancer therapy by researchers. Even with advances in science and technology, obstacles and major problems in prostate cancer care are drug resistance against anticancer drugs, difficult stem cell targeting, side effects of anticancer actives, low therapeutic window of anticancer drug, lack of tools, and cost as a critical factor for cancer diagnosis, etc. As we know, the most modern therapies for prostate cancer are viz. radiation therapy, chemotherapy, surgery, more recently enrolled immunotherapy as well as immune regulation therapy that frequently destroys healthy cells and triggers severe side effects, hence proved to be ineffective for certain patient populations (von Roemeling et al. 2017). Besides this, the maximum allowed dose of anticancer actives is also limited (Agarwal et al. 2019).

Often large doses of drugs are needed to prevent widespread cancer in different tissues and bodies that are economically unfeasible and create extreme toxicity (Padhi et al. 2020). Concisely, its un-specificity in cancerous cells is the most unifying trait that restricts anticancer drug delivery to a tumor mass. Unfortunately, an anticancer agent cannot differentiate between healthy cells and cancer cells. Therefore it functions together with cancer cells in healthy cells. The high tissue distribution and the accumulation of anticancer drugs in other organs is another consideration in cancer treatment. Consequently, a higher number of doses are to be given to exploit the therapeutic reaction and consequently results in severe side effects and toxicity (Gad et al. 2016). On the other hand, physiochemical property includes poor solubility of anticancer drugs which accounts for lower bioavailability that affects the overall performance of active. On the contrary, the high solubility of anticancer candidates is accounted for speedy elimination from the patient's body (Arya et al. 2019).

Despite the revolutionary merits of engaged anticancer therapies, the defeat of cancer treatment at an advanced point of prostate cancer, and the huge expansion of multiple drug resistance is the foremost barrier (Espinosa-Cano et al. 2018). Additionally, the existence of intra-tumor heterogeneity is an additional concern to the aggressive prostate cancer expansion. Unfortunately, in most cases, prostate cancer reoccurrences have been observed after the complete cancer treatment. Overall, nanocarrier-mediated co-delivery is the major objective of groundbreaking and successful anti-cancer chemotherapy (Arya et al. 2019; Parveen and Sahoo 2008; Padhi et al. 2015). Another prostate cancer treatment strategy includes prodrugs due to admirable stability at biological fluids (viz. blood) and it is less toxic than its activated form. Interestingly, it exhibits low toxicity due to the activation of the product within the targeted prostate cancer tumor microenvironment (Ast 2003). In another pioneering work, prostate cancer tumor-related peptidase enzymes (prostate-specific antigen) have been reported in the activation of prodrugs. Unfortunately, it shows the one-third metabolism of the prodrug into an active form (DeFeo-Jones et al. 2000).

Recently, targeted treatments for prostate cancer have been reported by various studies that concentrate on focusing on anomalies but there are also some limits. Unfortunately, hormone therapies do not respond to androgen-independent prostate cancer. In addition, immunotherapy is much costly than the other techniques and has lower success rates because of less assurance of the related improvement in immune performance. Furthermore, anticancer molecules used in particular for prostate cancer are poorly bioavailable and are insufficient to use. Consequently, an appropriate drug-delivery vehicle is desired as a modification substratum to bind target ligands/receptors (Salaam et al. 2018). Novel chemotherapies are tremendously implemented in new advances that can improve the abilities of medications by hitting cancer cells either passively or actively (Parveen and Sahoo 2008; Behera and Padhi 2020). In that, passive targeting utilizes the tendency of cancer cells to collect anticancer-loaded nanocarriers with the enhanced permeability and retention effect (Agarwal et al. 2019; Khuroo et al. 2014). The molecules-conjugated nanostructures that entangle the prostate cancer antigen or appropriate receptor overexpressed to cancer cells become actively targeted approach (Peer et al. 2007).

Recently, nanocarrier frameworks can also be divided into three groups based on the manner chemotherapeutic/anticancer agent is targeted at cancer cells and their specific physicochemical properties (Agarwal et al. 2019). In brief, the first nanocarrier frameworks consist of simple nanoparticles in the matrix and nanocapsules in the reservoir form (Jiashi et al. 2009). Furthermore, the second series of the nanostructure is laminate by types of polymers that exhibit over-expressed cancer cell-specific binding sites (Peer et al. 2007). In recent years, polymeric nanoparticles linked to preferred ligands, are widely used for detection in the three generation series. Recently reported publications to support the fact that this two generations series of remarkable polymeric nanoparticles target the prostate tumor through an active targeting approach (Agarwal et al. 2019; Peer et al. 2007).

16.2 The Emerging Era of Polymeric Nanoparticles

Nanoscale materials are perfect candidates being used as platforms for drug delivery for targeted treatment of cancer. Recent developments in nanotechnology have led to the development of several nanostructures of different sizes, shapes, core physical, and surface properties under investigation for possible medical use, specifically for cancer therapy (Krishnan et al. 2010). Taken as a whole, nanotechnology has made substantial strides in cancer chemotherapy progress in the last ten years (Rivero-Buceta et al. 2019; Padhi et al. 2020). The use of nanoparticles allows reduced doses of the drugs administered (Salaam et al. 2018). Fascinatingly, nanotechnology is opening the solution to accomplish and improve the performance and sustainability limitations of traditional delivery systems. From the very beginning, nanoparticles have emerged as a possible candidate for the delivery of therapeutic agents to specified organs, tissues/cells, and for minimizing drug delivery problems (Parveen and Sahoo 2008; Verma et al. 2017). A further important categorization of nanoparticles is inorganic nanoparticles and polymeric nanoparticles centered on their compositional structure (Khalid and El-Sawy 2017). In this subsection, the emerging era of polymeric nanoparticles has been discussed in brief.

Interestingly, polymeric nanoparticles are colloidal particles (submicron) that are preferred for the distribution of medicinal items (actives) to the targeted site. It may be of different shapes including spherical, branched, and core-shell. Generally, polymeric nanoparticles are synthesized using formulation techniques such as solvent evaporation, solvent diffusion, spontaneous emulsification, polymerization, and many more methods. In polymeric nanoparticles, the targeted anticancer drug is usually adsorbed/conjugated or encapsulated inside or on the surface of the nanoparticles for specific/targeted drug delivery (Kumari et al. 2016).

In particular, targeted polymeric nanoparticles efficiently deliver the anticancer agent to a specific location in a controlled manner. Therefore it offers the efficient therapeutic potential for cancer treatment with minimal toxicity to normal cells (Khalid and El-Sawy 2017). Overall, polymeric nanoplatform containing polymers is the most extensively used material in biomedical sciences, engineering as well as in our daily lives. Additionally, the implementation of such polymers is linked directly to their properties (viz. cross-linking nature, hydrophilicity, suitable functional group presence) especially in health engineering (Reddy and Rao 2016). Owing to this, it offers the ultimate benefits of stability, entrapment efficiency, biocompatibility, safety, drug loading, etc. Additionally, advances in polymer chemistry and colloid polymer chemistry have brought unbelievable perspectives into the domain of drug delivery (Fig. 16.2). Therefore, this could be used as a feasible medium for different cancer applications by customizing and influencing the attributes of nanomaterials (Vauthier and Bouchemal 2009). For example, nanospheres and nanocapsules have been typically used for anticancer drug delivery. In that, the nanosphere allows adsorption of the anticancer agent onto the particulate surface that is prone to degradation due to intensive processing (Peer et al. 2007).

Fig. 16.2

Prostate cancer: hurdles for prostate cancer drug delivery and desirable properties of polymers for designing of polymeric nanoparticles for targeted delivery in prostate cancer. The tumor microenvironment in case of prostate cancer like high vasculature, high temperature, decrease in oxygen, change of pH surrounding the cancer cells to acidic pH, lack of adhesion, irregular shape, high cell density and biofilm layer limits for targeted delivery of anticancer drugs. Hence the polymeric nanoparticles are designed in such a way to deliver the chemotherapeutic drugs following the pH-responsive release with low initial burst release of the drugs. Other mechanisms may include temperature-sensitive drug delivery, increase in adhesion of drugs to prostate cells, avoiding the anaerobic lysis and biofilm lysis

Furthermore, the surface structures can also be configured to facilitate high loading and improve payload distribution that can be beneficial for the management of prostate cancer. Moreover, numerous advances in the use of polymeric nanoplatforms with several approaches (coating/layer-by-layer) allow the anticancer drug/antigen to be released over many days in a regulated approach (Agarwal et al. 2019). To summarize, owing to these remarkable properties of polymeric nanoparticles, it accounts for an alternative substitute for the effective treatment of prostate cancer.

16.3 Surface Engineered Polymeric Nanoparticles for Prostate Cancer

For effective drug delivery to the targeted site of prostate cancer, different types of polymeric nanoparticles can be effectively employed in prostate cancer therapy. As we know, the biological complexity in the body requires an appropriate root for nanocarriers. Therefore, polymeric nanoparticles are engineered to accumulate passively or actively in prostate cancer tumor sites, by regulating their hydrodynamic properties or by using target molecules to activate the surfaces of polymers. Concerning that, there are mainly two ways to surface engineer polymeric nanoparticles targeting prostate cancer, namely passive targeting, and ligand-centered targeting, to deliver anticancer molecules at the desired site (Fig. 16.3).

Fig. 16.3

Targeted (active targeting) and non-targeted (passive targeting) strategies for designing nanoplatform and its application for anticancer agent targeted delivery. Active targeting of polymeric nanoparticles is based on recognition of ligand conjugated drug by overexpressed receptors on the tumor cells. The drug gets internalized by receptor mediated endocytosis. Passive targeting of polymeric nanoparticles help to enhance the permeability and retention (EPR) effect. Accordingly, it enhanced the deposition and retention of the anticancer drug (high molecular weight) in prostate cancer solid tumors.‘Reprinted with permission of “Current trends and challenges in cancer management and therapy using designer nanomaterials”, Nano Convergence, Springer Nature from (Navya et al. 2019)

16.3.1 Passive Targeting

In passive targeting of anticancer molecules for efficient management of prostate cancer, the anatomical variations within normal and prostate cancer tumor tissue are utilized to deliver drugs for prostate cancer (therapeutic site) (Arya et al. 2019; Famuyiwa and Kumi-Diaka 2018). It may due to prostate cancer tumor vasculature, which varies significantly from normal prostate tissues. Generally, prostate cancer tumor contains heterogeneous cells of high vascular density and are generally larger sized. Additionally, the prostate cancer tumor is more permeable or leaky unlike the compact endothelium of typical blood vessels. Furthermore, widespread vascular mediator (viz. prostaglandins, bradykinin, vascular endothelial factor, nitric oxide, etc.) development facilitates the extravasations, despite the abovementioned pathophysiological conditions involving temperature, pH, and surface charge of prostate tumor. Passive targeting of polymeric nanoparticles for prostate cancer management has also been considered as an appropriate substitute for anticancer drug delivery (Arya et al. 2019; Hema et al. 2018). In this sub-section, we have emphasized architectured polymeric nanoparticles based on non-targeted drug delivery for prostate cancer management.

In passive targeting of polymeric nanoparticles for prostate cancer management, the enhanced permeability and retention effect enhanced the deposition and retention of the anticancer drug (high molecular weight) in prostate cancer solid tumors (Fig. 16.3). Generally, nanoparticular frameworks are still used to implement passive targeting when prostate cancer tumor volume raises the specific pathophysiological features of tumor vessels. Prostate cancer results in an increased enhanced permeability and retention effect, thanks to the leaky vasculature of the tumor and poor lymphatic flow (Arya et al. 2019).

As the dimensions of polymeric nanoparticles are usually smaller than those of the perforated blood vessels, they get accumulated in cancerous cells and stay stuck inside these tumors due to greater retention capacity as compared to normal tissues (Hema et al. 2018). Ample literature claimed that the microenvironment around the prostate cancer cells is different from normal prostate cells, which offers the passive targeting of anticancer molecules. Besides, the metabolic rate is also superior in prostate cancer cells. Furthermore, the acidic pH in the microenvironment is observed owing to the high use of glycolysis by cancer cells to retain the supply of oxygen and types of nutrients (Morshed et al. 2018). Besides, the assorted types of enzymes present in prostate cancer and the temperature of prostate tumors are furnished with the passive targeting of anticancer molecules (Arya et al. 2019; Hema et al. 2018). Owing to this, the pH-responsive polymeric nanoparticles, temperature-sensitive polymeric nanoparticles, and enzyme responsive release of the anticancer agent from polymeric nanoparticles are gaining much attention from research scholars, which provides numerous merits over the conventional anticancer dosage forms.

The surface potential of tumor cells is highly negative than normal cells (Morshed et al. 2018). Therefore, the positive zeta potential of polymeric nanoparticles is majorly used for designing anticancer-targeted delivery, which offers cellular internalization as well as the subcellular localization of polymeric nanoparticles due to electrostatic binding forces. Finally, it is responsible for the overall cytotoxicity potential of selected anticancer molecules (Arya et al. 2019; Hema et al. 2018). Therefore, passive targeting is a superb way to engineer polymeric nanoplatform for well-organized prostate cancer treatment.

16.3.2 Ligand-Based Targeting

Abundant literature claimed that certain intracellular and extracellular receptors are over-expressed by the prostate tumor surface. Therefore, the targeting of these prostate cancer cell receptors may be desirable for the high deposition of the anticancer drug into prostate cancer tissue/cells. Targeting prostate cancer through architectured polymeric nanoparticles is an appealing prospect to deliver anticancer drugs owing to their aptitude to deliver active at specific locations/sites, consequently shielding normal cells or tissues from severe toxicity. Promising targets in prostate cancer have been folate receptors, prostate-specific membrane antigen, neuropilin-1 receptors, and transferrin receptors (Arya et al. 2019). In this type, ligands are integrated into the surface of the architectured polymeric nanoparticles system, this form of targeting connects with the right receptor at the desired prostate cancer tumor site. Fascinatingly, several kinds of ligands such as an antibody, peptides, aptamers, vitamins, carbohydrates, other small molecules, etc. (Fig. 16.4) have been selected in designing targeted architectures of polymeric nanoparticles for prostate cancer management (Agarwal et al. 2019; Hema et al. 2018). Ligand-based targeting can be implemented through the surface functionalization of the polymeric nanoparticles containing anticancer drugs, along with selected targeting moieties, which selectively recognize receptors/antigens of prostate cancer cells, increase their therapeutic effectiveness, and transcend multidrug resistance of cancer cells (Arya et al. 2019; Hema et al. 2018). Overall, ligand-based targeting offers notable merits including the release of anticancer molecules to the prostate cancer cells. It may form bonding with the cancer cell membrane and sustain/control the anticancer drug release or it can be internalized into prostate cancer cells via endocytosis mechanism.

Fig. 16.4

Active targeting of architecture polymeric nanoparticles by overexpressed receptors and ligands for prostate cancer management. Ligands such as an antibody, small molecules, proteins/peptides, and aptamer are integrated on the surface of the polymeric nanoparticles, which offers the targeting with the right receptors such as aptamer, proteins/peptide, antibodies, etc. at the desired site of prostate cancer

16.4 Polymeric Nanoparticles for Targeting Prostate Cancer

There are currently several approaches available to produce targeted polymeric nanoparticles that incorporate a variety of theranostic molecules via the chemical process for prostate cancer management. Polymeric nanoparticles have shown tremendous potential in terms of the creation of polymeric nanoplatforms for prostate cancer molecular imaging, theranostics, etc. as stated in this section.

16.4.1 Solid Dispersion of Polymeric Nanoparticles

From their inception, solid polymeric nanoparticles are gaining huge attention from research fraternities, owing to their notable merits. Natural polyphenol viz. resveratrol is well known for its numerous biological/anticancer effects on different human cell lines of cancer. However, low water solubility, limited bioavailability, and poor stability hinder its effectiveness in the battle against prostate cancer. A plentiful literature survey divulged the targeting ability (active/passive) of poly (lactic-co-glycolic acid) against assorted cancer types. Owing to this, Nassir et al. had developed resveratrol-loaded poly (lactic-co-glycolic acid) nanoparticles using polylactic-co-glycolic acid and resveratrol through nanoprecipitation technique. Herein, resveratrol loaded poly (lactic-co-glycolic acid) nanoparticles showed a significant decrease in cell viability against prostate cancer cells (LNCaP cells) with inhibitory concentration upto 50% and 90% (IC₅₀ and IC₉₀) of 15.6 μM and 41.1 μM, which may be due to apoptosis, the hammering of the potential of mitochondrial membrane, reactive oxygen species production in LNCaP cells, deoxyribonucleic acid nicking, etc. Finally, this polymeric platform exhibited notable cytotoxicity in prostate cancer cells (LNCaP cells) as compared to plain resveratrol. Overall, Nassir et al., suggested that the resveratrol-loaded poly (lactic-co-glycolic acid) nanoparticles can be used in chemotherapy owing to their remarkable safety to normal prostate cells (Nassir et al. 2018).

As we know, in conjunction with immune stimulant adjuvant, precise immunotherapy seems to be an important technique to facilitate tumor regression and avoid recurrences in prostate cancer. A pioneering study reported the tumor-associated antigens (source-murine prostate cancer cell lines TRAMP-C2) encapsulated oral microparticulate vaccine using hydroxyl propylmethyl cellulose and ethyl cellulose through a spray dryer. This polymeric nanoplatform showed size-dependent cellular uptake that confirmed the principal role of particle size in antigen delivery. Additionally, the stability and protection of antigen from high acidic pH were achieved through a polymeric platform. The cyclophosphamide and granulocyte macrophage-colony stimulating factor combination with microparticulate vaccine offered a fivefold reduction in prostate cancer tumor volume in mice. Thus, oral microparticle vaccines can trigger a robust cell tumor response, with a substantial amount of resistance against tumor growth and progression in combination with clinically relevant agents (Parenky et al. 2019). Bharali et al. designed docetaxel-poly(ethylene glycol)-based poly (lactic-co-glycolic acid) nanoparticles using the solvent diffusion method and further engineered the surface of nanoparticles through conjugation of anti-CD24 for prostate cancer targeted delivery of docetaxel. In this, engineered nanoparticles demonstrated higher accumulation (~tenfold) in prostate cancer in contrary to non-conjugated nanoparticles, and accordingly reduced the overall prostate tumor mass and its viability. Herein, poly (ethylene glycol) offered longer time stability in blood circulation through minimizing opsonization. Additionally, high molecular weight poly (ethylene glycol) offers the maleimide functionalities for anti-CD24 conjugations. Enchantingly, nanoparticles played the role of nano-reservoir for docetaxel with sustained-release kinetics over an extended time. To conclude, the sustained release targeted docetaxel-poly(ethylene glycol)-based poly (lactic-co-glycolic acid) nanoparticles served as a docetaxel reservoir for a long duration, and thus, the nanoparticles may be able to remove the repeated doses of docetaxel in prostate cancer treatment (Bharali et al. 2017).

Singh and co-authors claimed a higher level of folate receptor expression in prostate cancer tissues (obtained from the patient) as compared to the normal tissue of the human body. Keeping this in mind, the authors developed the folic acid conjugated resveratrol – docetaxel nanoparticles using fluorescein sodium salt and starch by planetary ball mill and further coated it with polycaprolactone and poly (ethylene glycol). It demonstrated that the nanoparticles resulted in 65.90% apoptosis, which was higher than the single anti-cancer molecule. Additionally, immunofluorescence studies confirmed the enhancement in intracellular concentration of resveratrol and docetaxel in the cytoplasm was due to receptor-mediated endocytic delivery of the entrapped drug. Moreover, polycaprolactone- poly (ethylene glycol) copolymer demonstrated greater hydrophilicity and degradability than polycaprolactone polymer, which was confirmed from cell culture studies. In addition, resveratrol/docetaxel coating with polycaprolactone- poly (ethylene glycol) boosted the bioavailability and sustained the release of resveratrol/docetaxel. For this reason, this research gave a promising insight into the biomedical use of resveratrol and docetaxel-based nanoparticles for prevention and treatment (Singh et al. 2018). A shortage of an efficient delivery vector appeared as a key obstacle in developing efficient ribonucleic acid interference therapy. In 2017, Evans et al. designed the folate targeted amphiphilic cyclodextrin with di-stearoyl phosphatidyl ethanolamine poly (ethylene glycol) 5000-folate for precise targeting delivery of ribonucleic acid interference to prostate cancer cells. The endosomal release of small interfering RNA was achieved by using pH-sensitive synthetic fusogenic peptide GALA that contains amino acid (30) endosomal escape peptides. Herein, the uptake of RNA interference-loaded cyclodextrin nanoparticles has been reduced by incubation of excess free folate. In conclusion, it was inferred that the folate targeted amphiphilic cyclodextrin vector would be a suitable candidate for effective prostate cancer treatment (Evans et al. 2017).

Fitzgerald et al. designed the small interfering ribonucleic acid and cyclodextrin complex. Further, PEGylated adamantane was conjugated with an anisamide-targeting ligand that helped to target the sigma receptor of prostate cancer cells. Finally, developed nanosized functionalized complex offered stability and protection to small interfering ribonucleic acid from serum-induced nuclease degradation. Additionally, in vitro study confirmed that the targeted complex offered superior cellular uptake as well as knockdown of the PLK1 gene in prostate cancer cells. To our awareness, it would be the only evidence that cyclodextrin had been used to deliver small interfering ribonucleic acid to prostate cancer cells through their sigma-receptor in the form of integration complexes with adamantane derivatives. Therefore, in the future, it could be a suitable carrier for the targeted treatment of prostate cancer (Fitzgerald et al. 2016). In another pioneering work, Zhang and co-investigators designed small hairpin ribonucleic acid-loaded polymeric nanoparticles and used them as folate receptor-targeted nanoparticles by utilizing a folate-targeted H1 nanopolymer for hairpin ribonucleic acid delivery. Herein, androgen receptor-targeted hairpin ribonucleic acid significantly suppressed prostate cancer growth with a prolonged survival rate in hormone-independent prostate cancer tumor-bearing mice. This study confirmed that the nanoparticles inhibited deoxyribonucleic acid damage repair signaling pathways. These nanoparticles increased the sensitivity of hormone-independent prostate cancer to radiotherapy. Therefore, developed nanoparticles can be preferred as a radiosensitizer in hormone-independent prostate cancer, which can maintain superior treatment aptitude. In the future, such therapy can be combined with dose-escalated radiotherapy for better treatment against treatment-resistant prostate cancer (Zhang et al. 2017b).

Dhas and colleagues developed stable, nanosized bicalutamide-loaded folic acid conjugated chitosan functionalized poly (lactic-co-glycolic acid) nanoparticles through the nanoprecipitation method for prostate cancer management. In brief, folic acid and chitosan conjugate were fabricated to coat nanoparticles, which sustained the release of the drug for 120 h. Besides, the cell proliferative assay was confirmed by the dose-dependent cell cytotoxicity. Herein, folic acid functionalization enhanced the folate receptor binding ability of developed nanoparticles. Furthermore, developed nanoparticles accomplished remarkable cell viability (56.4%) than non-functionalized nanoparticles (43.8%). Overall, the cell proliferative assay confirmed that nanoparticles enhanced the therapeutic efficacy and demonstrated higher cell cytotoxicity as compared to plain drug and non-functionalized nanoparticles (Dhas et al. 2015). Huerta and co-authors developed spherical, nanosized, and stable nimesulide-loaded nanoparticles prepared from poly (lactic-co-glycolic acid) and eventually coated them with chitosan through the emulsion-solvent evaporation method. In brief, stronger interaction with the cell membrane resulted due to the positively charged surface, which further helped to increase the in vitro nanoparticles uptake. Besides, prepared polymeric nanoparticles displayed remarkable PC-3 cell growth inhibition. Furthermore, nanoparticles showed interference in the permeability of nimesulide, and consequently resulted in low carrier cytotoxicity, whereas it preserved the overall pharmacological potential of the encapsulated active. Hence, nanoparticles would be a co-adjuvant therapy for prostate cancer treatment, that can offer the targeted delivery through intratumor injection (Huerta et al. 2015). Therefore, solid polymeric nanoparticles can be preferentially used for prostate cancer treatment through passive as well as active targeting due to their tunable and versatile properties and remarkable merits over the conventional carriers.

16.4.2 Conjugated Polymeric Nanoparticles

As per literature, docetaxel appears to be a reliable therapy option that improves metastatic castration-resistant prostate cancer longevity and the quality of life of patients. While clinical trials with docetaxel-based therapy have been successful, total estimated toxicity and drug resistance restrict their therapeutic applications over the long-term period. In 2014, Hoang et al. evaluated the efficacy and safety of docetaxel through bone metastatic models of castration-resistant prostate cancer and subcutaneous by reformulating the docetaxel and poly (ethylene glycol) conjugated carboxymethylcellulose polymeric platform or cellax. In brief, carboxymethylcellulose was modified via acetylation, which offered superior conjugation ability, high yield, solvent solubility, and conjugation reproducibility. The acetylated carboxymethylcellulose, docetaxel, and poly (ethylene glycol) were used to develop cellax. The cellax nanoparticles were developed through a controlled nanoprecipitation method (Fig. 16.5).

Fig. 16.5

Cellax polymer synthesis that contains poly (ethylene glycol) (PEG) as a steric stabilizing shield. Development of cellax nanoparticles (cellax NPs) followed by loading of docetaxel for prostate cancer management has been reported. At first, carboxymethylcellulose has been modified using the acetylation method that gives the superior conjugation ability. The acetylated carboxymethylcellulose, docetaxel, and poly (ethylene glycol) have been used to develop cellax. Finally, the cellax nanoparticles have been developed through a controlled nanoprecipitation method in presence of sodium chloride (NaCl). Reprinted with permission of “Docetaxel–carboxymethylcellulose nanoparticles display enhanced anti-tumor activity in murine models of castration-resistant prostate cancer”, Elsevier, from (Hoang et al. 2014)

Encapsulating docetaxel in nanoparticles extended their pharmacokinetic properties greatly and enhanced docetaxel bioavailability. Lastly, the enhanced permeability and retention effect of nanoparticles increased the tumor concentration of docetaxel, while limiting the overall systemic toxicity. Herein, the use of polymeric nanoparticles for docetaxel delivery offered the ability to deliver an eightfold high concentration of drug to mice with a reduction in previously reported side effects. It indicated the fact that cellax exhibited negligible side effects contrary to native molecules. In addition, cellax improved two to threefold survival rate followed by a notable increment in quality life of the mouse (model: prostate cancer metastases to bone). These findings offered a good promising viewpoint on the future translation of cellax to enhance metastatic castration-resistant prostate cancer treatment (Hoang et al. 2014).

Following docetaxel failure, cabazitaxel was recommended for metastatic castration-resistant prostate cancer, but still, the survival enhancement was only modest. Hoang et al. developed polymeric cabazitaxel conjugated nanoparticles for metastatic castration-resistant prostate cancer using cellx as a polymer that formed cabazitaxel conjugated cellax polymeric nanoparticles. Herein, owing to the high drug loading ability, biocompatibility, and safety of carboxymethylcellulose, carboxymethylcellulose-centered polymeric nanoplatform was synthesized. Interestingly, it reduced the overall toxicity due to the sustained release of cabazitaxel. Without initial burst release, polymeric nanoparticles sustained the cabazitaxel release in serum (10%/day). Consequently, it offered a 157-fold higher delivery of cabazitaxel to the docetaxel-resistant PC3 model of prostate cancer (PC3-RES), which was a 25-fold high dose than the pure cabazitaxel. Owing to that, it exhibited superior tumor inhibition in docetaxel-resistant castration-resistant prostate cancer mice models. Prepared nanoparticles demonstrated a tremendous potential to enhance metastatic castration-resistant prostate cancer therapy over therapeutically certified cabazitaxel (Hoang et al. 2017). Thus, conjugated polymeric nanoplatform with anticancer molecules offered minimal toxicity to normal cells, controlled/sustained release, good bioavailability, and accordingly superior prostate cancer tumor inhibition potential.

16.4.3 Polymer-Lipid Hybrid Systems

The newly reported form of malignancy in males is prostate cancer and for efficient prostate cancer treatment, combined chemotherapy has proven to be a successful method. About this, Chen et al. reported the co-delivery of curcumin: cabazitaxel system, aptamer conjugated curcumin, and cabazitaxel co-delivered lipid-polymer hybrid nanoparticles using aptamer conjugated poly (lactic-co-glycolic acid) – poly (ethylene glycol) and l-α-phosphatidylcholine from soybean (lipid system). The designed hybrid lipid-polymer nanoparticles provided the polymeric core and lipidic shell for anticancer molecules. Besides this, the aptamer conjugation in the hybrid system offered targetability towards the prostate cancer tumor cells. Owing to the smaller nanosized dimension (200 nm) of developed nanoparticles, it exhibited appreciable cytotoxicity and longer systemic circulation. In this hybrid system, poly (ethylene glycol) offered several merits including low immunogenicity, high flexibility, low toxicity, etc. The decoration of aptamer on the surface also assisted in sustaining the release of anticancer molecules. As result, these hybrid lipid nanoparticles sustained the release of curcumin and cabazitaxel. Herein, these drug-loaded nanoparticles accomplished good cell inhibition and superior prostate cancer tumor accumulation. Additionally, the curcumin: cabazitaxel (2:5) co-delivery system confirmed the potential of a hybrid lipid polymer nanoparticles system that offered synergistic effects for prostate cancer treatment. Hence, the concurrent administration of curcumin and cabazitaxel would open a new door for the efficient treatment of prostate cancer (Chen et al. 2020).

In another research work, Chen et al. synthesized cabazitaxel loaded bombesin-polyethylene glycol-1, 2-distearoyl-sn-glycero-3-phosphoethanolamine contained hybrid lipid-polymer nanoparticles. Cabazitaxel and bombesin-polyethylene glycol-1,2-distearoyl-sn-glycero-3-phosphoethanolamine have been used as polymer conjugated targeted ligand by employing the nanoprecipitation technique. These nanoparticles containing negative surface charge assisted in reducing the toxicity, which was important for prostate cancer therapy. The positive surface load enabled the hybrid lipid-polymer nanoparticles to efficiently get associated with the prostate cancer cell surface, promote cell penetration and facilitate the process of internalization. In vitro cytotoxicity of hybrid lipid-polymer nanoparticles demonstrated that the prepared nanoparticles were more efficient than the native form when evaluated in prostate cancer cell lines (LNCaP cells). Additionally, nanosized polymeric nanoparticles were conducive to passive tumor targeting due to enhanced permeability retention effects that resulted in successful tumor accumulation of nanosized polymeric nanoparticles. In general, the nanoparticles provided cancer cells with cabazitaxel sufficient to enhance the anti-tumor efficacy (Chen et al. 2016).

Recently, Yeh et al. also reported the synthesis of doxorubicin and vinorelbine-loaded liposomes. Doxorubicin and vinorelbine-loaded liposomes have been prepared through a thin lipid method and were further functionalized with SP204-polyethylene-1, 2-distearoyl-sn-glycero-3-phosphoethanolamine to form doxorubicin and vinorelbine loaded liposomes. Interestingly, surface-engineered nanoparticles demonstrated enhanced intracellular drug delivery with superior cytotoxicity due to the functionalization of the SP204 targeted peptide. Overall, targeted nanoparticles were observed to have remarkable antitumor activity as well as promoted the overall survival rate in the studied mice. Hence, targeted functionalized polymeric nanoplatform with the lipidic system had notable potential in engineering targeted drug delivery for the management of prostate cancer (Yeh et al. 2016). Concisely, a polymer-lipid hybrid system may be an appropriate candidate for intracellular anticancer drug delivery in prostate cancer management and other cancer treatment.

16.4.4 Polymeric Micelles

Polymeric micelles have been explored for the maintenance of therapeutic dosage levels at specific sites. Furthermore, polymeric micelles have covalent interlinking in the center and shell to enhance structural integrity and excellent stability. Feng et al. accomplished the synthesis of prostate-specific membrane antigen targetted nanosized and stable prostate cancer-binding peptide (modified glycol chitosan lipoic acid) based on docetaxel micelle using prostate cancer binding peptide modified glycol chitosan – lipoic acid conjugate and docetaxel using emulsion/solvent evaporation method (Fig. 16.6). Owing to cross-linking among composites, micelle offered a slower docetaxel release than the plain micelle. Additionally, the targeted micelle was able to achieve higher cellular uptake and cytotoxicity as compared to the non-targeted micelle. Furthermore, micelle showed stronger anticancer activity against LNCaP tumor xenograft models. Therefore, this combination study presented a novel perspective of effectively launching innovative targeted plus cross-linked polymeric micelles for delivery of a lipophilic anticancer agent for effective cancer treatment (Feng et al. 2019).

Fig. 16.6

Prostate-specific membrane antigen (PSMA) ligand conjugated docetaxel loaded small molecular ligand of PSMA-poly (ethylene glycol)-polycaprolactone (SMLP-PEG-PCL) micelle for prostate cancer cells (LNCaP cells) targeted therapy. Herein, the conjugation of the targeted ligand in docetaxel micelles shows the targeted delivery of docetaxel micelle into cancer cells as well as high cellular uptake. Reprinted with permission of “PSMA ligand conjugated poly(ethylene glycol)-polycaprolactone polymeric micelles targeted to prostate cancer cells”, PLoS ONE from (Jin et al. 2014)

In another pioneering work, Jin et al. designed the prostate-specific membrane antigen ligand conjugated docetaxel-polycaprolactone-polymeric -micelle for prostate cancer targeted therapy. The formulated stable and nanosized polymeric micelle accomplished the sustained release of docetaxel with remarkable stability over 7 days. As the ester group of polycaprolactone was liable to an acidic environment, the docetaxel release was found to be slow in pH 7.4 than the pH 5.5. Furthermore, the conjugation of the targeted ligand in micelles offered a lower IC₅₀ value as compared to the non-targeted micelles. Besides, it also achieved a fivefold higher cellular uptake. The observed results indicated the fact that the prepared nanosized micelle can be used for the targeted delivery of anticancer agents in prostate cancer treatment (Jin et al. 2014).

Repeated therapies involving chemical agents usually fail to achieve the required therapeutic efficacy because of cancer stem cells and micro RNA-regulated chemoresistance. The expression of micro RNAs can alter because of defective signaling pathways, including hedgehog signals. Previously published literature claimed that the concurrent administration of cyclopamine and paclitaxel successively inhibited the paclitaxel resistance cells. In 2017, a published pioneering study assembled the poly(ethylene glycol)-block-poly(2-methyl-2-carboxylpropylene carbonate-paclitaxel – graft dodecanol) and poly(ethylene glycol)-block-poly(2-methyl-2-carboxylpropylene carbonate- cyclopamine – graft dodecanol) polymer-drug conjugates using polyethylene glycol-block-poly(2-methyl-2-carboxylpropylene carbonate-graft dodecanol) into polymeric- cyclopamine @ polymeric- paclitaxel assembled micelles through film hydration method. Polymeric – cyclopamine @ polymeric – paclitaxel micelles achieved good stability, which offered lower burst release of cyclopamine and paclitaxel at pH 5.3 and 7.4. Furthermore, polymeric- cyclopamine @ polymeric- paclitaxel micelles containing ester bonding and amide bonding showed excellent stability at neutral pH which resulted in lower drug release (but not significant). Furthermore, the modification in pH from 7.4 to 5.3 resulted in the cleavage of both the abovementioned bodings in the prepared micelle. Interestingly, the polymeric- cyclopamine @ polymeric- paclitaxel micelles suppressed the prostate cancer tumor colony generation. Moreover, it also inhibited the hedgehog signaling plus upregulated prostate cancer tumor suppressor micro RNAs. The polymeric- cyclopamine @ polymeric- paclitaxel micelles therapy demonstrated significant prostate cancer growth inhibition in the orthotopic prostate tumors in selected mice. In the future, this combination i.e. polymeric – cyclopamine @ polymeric – paclitaxel micelles could be used for combating chemoresistance in prostate cancer therapy (Yang et al. 2017).

Liu and Huang synthesized brush type biodegradable and G3-C12 modified poly (oligo (ethylene glycol) mono-methyl ether methacrylate-co-G3-C12)-g-poly(e-caprolactone) using R-opening polymerization, reversible addition-fragmentation transfer polymerization, and polymer post-functionalization. Further, poly (oligo (ethylene glycol) mono-methyl ether methacrylate-co-G3-C12)-g-poly(e-caprolactone) was used for the delivery of bufalin that helped in castration-resistant prostate cancer-centered targeted treatment. The biocompatible and biodegradable micellar nanoparticles offered controlled release (about 62% after 24 h) of bufalin at pH 7.4 due to the degradation of esterase in the micelle. Further, it improved the overall anticancer efficacy in both studies. Herein, the G3-C12 incorporation in nanoparticles enhanced the inhibition of tumor growth (P < 0.05) in contrary to non-targeted nanoparticles. Owing to more cellular apoptosis and improved anticancer efficacy, these prepared micellar nanoparticles could be used as a potential substitute for castration-resistant prostate cancer treatment (Liu and Huang 2016). Therefore, in the future, polymeric micelle could be a choice for prostate cancer therapy due to the maintenance of therapeutic dosage levels at specific sites.

16.4.5 Polyplexes

In an attempt to comprehend the involvement of micro ribonucleic acid in vivo and to support tailored gene therapy for micro ribonucleic acid-associated prostate cancer, new developments in convenient micro ribonucleic acid delivery techniques using prostate cancer-driven nanoparticles have presented crucial details. In this esteem, Zhang and co-authors designed the polyarginine peptide (R11) – branched disulphide polyethyleneimine (SSPEI)-micro RNA-145 nanocarrier for the targeted delivery of micro RNA-145. In brief, R11 conjugated SSPEI (R11- SSPEI)-micro RNA-145 demonstrated bioactivity at a wide concentration range. Furthermore, it demonstrated the dose-dependent reduction in the reported signal that confirmed the functional action of micro RNA-145. The systemic administration of prepared polyplexes accomplished the dramatic inhibition of prostate cancer tumor growth followed by prolonged survival duration (Zhang et al. 2015). In the upcoming days, the established targeted polyplexes for systemic administration could be explored as potential nanocarriers for prostate cancer therapeutic utilization.

16.4.6 Miscellaneous Polymeric Nanoparticles

The life-threatening systemic cytotoxicity of approved anticancer agents in normal cells/tissues is among the significant issues for impactful cancer chemotherapy. Plentiful literature divulged the polymeric nanocapsules that offered astonishing merits including the protection of enzymatic degradation of active molecules, the stability of drug molecules, excellent loading of the hydrophobic drug (in the oily core of nanocapsules), etc. Additionally, it modified the pharmacokinetics of anticancer agents and lowered normal cell toxicity. In 2020, the Shitole group developed quercetin and docetaxel-based polymeric nanocapsules using luteinizing-hormone-releasing hormone as an active target), poly (ethylene glycol) (as a spacer), and poly (lactic-co-glycolic acid) through interfacial deposition method with an optimized molar ratio of docetaxel: quercetin (1:3). Herein, polymeric nanocapsules offered the sustained release of active and poly (ethylene glycol) provided stability to nanocapsules in serum. Prostate cancer cell lines (PC-3 and LNCaP) confirmed the targetability of the luteinizing hormone-releasing hormone. Besides, the combination of docetaxel: quercetin incorporated polymeric nanocapsules showed superior cell inhibition activity than the single drug-loaded nanocapsules.

Further, polymeric nanocapsules exhibited higher cell toxicity than non-targeted polymeric nanocapsules. Therefore, optimized polymeric nanocapsules may be a preferential choice for the successful treatment of prostate cancer (Shitole et al. 2020). Concisely, the employment of polymeric nanocapsules in the domain of prostate cancer treatment has shown to exhibit a transformative effect. Additionally, it also improved the stability of anticancer molecules viz. peptides, hydrophobic agents, etc. The high surface area of polymeric nanoparticles permits the superior loading of anticancer agents and also allows for targeted delivery with minimal leakage of drugs in the biological environment. Architectured polymeric nanoplatforms targeted treatments of prostate cancer have been summarized in Table 16.1.

Table 16.1 Architectured polymeric nanoplatforms targeted treatment of prostate cancer

16.5 Stimuli-Responsive Polymeric Nanoparticles

The exploitation of biodegradable polymer-centered architectured nanocomposites (i.e. polymeric nanoparticles) as emerging drug delivery vehicles has received considerable interest in recent years. Regrettably, albeit with architectured polymeric nanocarriers at the prostate cancer tumor site, bioavailability, and release of drugs seemed difficult to control. Fascinatingly, these polymeric nanoparticles are believed to be potentially efficient therapeutic carriers to respond to inimitable external stimuli (Alsehli 2020). Therefore, to deal with this predicament, effective methodologies have been preferred to synthesize a stimulus (viz. light, temperature, pH, redox potential, etc.) responsive polymer nanocarrier, which demonstrates the response to prostate tumor-containing stimulus reactions (Fig. 16.7).

Fig. 16.7

Endogenous and exogenous stimuli-responsive polymeric nanoparticles for prostate cancer management. Effective methodologies have been preferred to synthesize endogenous stimuli enzymes, glutathione, pH, etc. for release of drug to the targeted site. In another case, exogenous stimuli mainly light, temperature, and ultrasound have been reported as responsible for drug release to the targeted site of prostate cancer

Briefly, the literature reported the fact that the altered pH value observed under pathologic conditions (acidic pH of prostate tumor microenvironment) has been widely preferred to encourage anticancer molecules to be released into a target biological or intracellular organ of prostate tumor (Mura et al. 2013). Similarly, in the case of temperature, due to their phase-transition compliance concerning temperature variations, temperature-responsive polymers have been extensively examined for smart drug delivery in cancer management. In this perspective, the temperature functions as an external/internal stimulus (Mohammed et al. 2018). A responsive nanoarchitecture polymeric nanocarrier offers the switchable release of anticancer molecules. In this, the actual difference in oxidizing extracellular and reducing intracellular space potential furnishes the triggered (controlled/sustained) release of anticancer molecules (Zhang et al. 2017a).

As we know, prostate cancer is among the most aggressive diseases and is distinguished by the over-expression of various enzyme forms, which are either connected to or secreted by the membrane (Barve et al. 2014). The utilization of enzymes (natural biological) as triggers to activate anticancer molecule release by weakening certain bonds to disassociate the architecture of polymeric nanoparticles structures thereby offering new approaches to prostate cancer management (Barve et al. 2014; Isaacson et al. 2017).

16.5.1 pH-Responsive Polymeric Nanoparticles

Literature referred to the fact that ginsenoside compound K (protopanaxadiol metabolite) has noteworthy anticancer activity. Not withstanding these characteristics, ginsenoside compound K's weak low solubility and low permeability dramatically reduces its efficiency and thereby restricts its therapeutic use. In, 2020 Zhang et al. developed the ginsenoside compound K – O-carboxymethyl chitosan nanoparticles using ginsenoside compound K and O-carboxymethyl chitosan through the ionic cross-linking method. Further, these prepared spherical polymeric nanoparticles demonstrated the remarkable particle size and polydispersity index, that helped for permeability enhancement. The negative zeta potential of nanoparticles indicated the superior stability of nanoparticles in dispersion. Besides, nanoparticles exhibited the pH-dependent (pH: 5.8) sustained drug release (58.56%, up to 96 h), which may be due to the protonation of O-carboxymethyl chitosan containing amino groups present in lower acidic pH. Furthermore, nanoparticles enhanced the cytotoxicity and cellular uptake of ginsenoside compound K in selected prostate cancer cell lines (PC3 cells). Additionally, nanoparticles boosted caspase-3 and caspase-9 activities. Therefore, a polymeric nanoplatform involving nanoparticles would be an exceptional nanocarrier for effective prostate cancer management (Zhang et al. 2020).

In 2017, Yan et al. reported the synergistic effect of epidermal growth factor receptor peptide also known as GE11 targeted and pH-responsive co-delivery of docetaxel and curcumin for prostate cancer management. In this context, GE11 conjugated poly lactic-co-glycolic acid –poly (ethylene glycol) conjugate was synthesized via cross-linking of GE11, polylactic-co-glycolic acid – poly (ethylene glycol) – maleimide. Curcumin and docetaxel-loaded G11 nanoparticles were prepared using poly (lactic-co-glycolic acid) – poly (ethylene glycol) – epidermal growth factor receptor peptide, GE11 conjugated poly (lactic-co-glycolic acid) –poly (ethylene glycol), and docetaxel via solvent displacement method. Herein, nanoparticles demonstrated 85.2% of the cumulative release of curcumin, which followed a sustained release at pH 5. Whereas, docetaxel release was found to be mild pH-dependent. Interestingly, the engineered nanoparticles containing cis-aconitic anhydride bonds helped to enable the release of curcumin/docetaxel from prepared nanoparticles via bond cleavage at pH < 6.5. Furthermore, it improved the cancer cell inhibition rate and tumor tissue growth. Hence, docetaxel and curcumin prodrug can open a novel perspective for prostate cancer treatment through concurrent GE 11 targeting along with enhanced permeability and retention effect of polymeric nanoparticles (Yan et al. 2017).

Reports cited the fact that usage of curcumin is limited for treating cancer because of its quick oxidative degradation, causing poor stability and bioavailability, in physiological conditions. In 2015, Thangavel and co-authors had developed curcumin encapsulated nanoparticles, which additionally provided the radical scavenger effect. Interestingly, pH-sensitive curcumin encapsulated pH-sensitive redox nanoparticle were designed using self-assembling methoxy-poly (ethylene glycol)-b-polylactide (i.e. amphiphilic block co-polymers) employing poly (ethylene glycol) – b – poly [4-(2,2,6,6-tetramethylpiperidine-1-45oxyl) aminomethylstyrene]) conjugated with reactive oxygen scavenging nitroxide radicals. They claimed that the entrapment of curcumin and nitroxide radicals suppressed the curcumin degradation in physiological conditions. Herein, drug release from nanoparticles at pH 7.4 was found to be slower and 60% of the curcumin remained encapsulated in micelle even at 72 h. Furthermore, nanoparticles induced strong apoptosis than native curcumin. Besides, prepared nanoparticles increased the bioavailability and significant reactive oxygen species scavenging activity that resulted in the suppression of prostate cancer tumor growth. Therefore, prepared nanoparticles can be a suitable alternative to overcome the aforementioned limitations to heighten their overall therapeutic potential (Thangavel et al. 2015).

Pearce and co-authors engineered the glutamate urea hyper branched polymer conjugated-doxorubicin-polymeric microparticles using glutamate urea as a prostate-specific membrane antigen targeting ligands and poly (ethylene glycol) hyper branched polymer. The loading of doxorubicin onto hyper branched polymer through hydrazone formation offered the controlled release of doxorubicin. These nanoparticles exhibited the pH-dependent (simulated endosomal conditions) in vitro release (90%) over 36 h. In total, this developed hyperbranched polymer confirmed the feasibility of controlled plus stimuli-responsive doxorubicin delivery for prostate cancer treatment. Herein, the hydrolysis of the hydrazone bond offered doxorubicin release in the endosome, which imparted cytotoxicity and triggered apoptosis.

Interestingly, after conjugation of ligand on the surface of the hyperbranched polymer, the developed polymeric nanoparticles demonstrated the concentration and time-dependent cellular uptake. Therefore, the hyperbranched polymeric approach is an exceptional theranostic for prostate cancer treatment and there is a requisite to explore it in clinically relevant models (Pearce et al. 2017). Despite the merits of established methods and technologies, resistance in cancer therapy is still challenging for scientific fraternities. In recent decades, zein (plant protein) is majorly preferred for designing tunable drug delivery as a carrier form.

In 2017, Thapa et al. designed a dual drug-loaded polymeric nanoplatform for the treatment of metastatic prostate cancer. Herein, stable, nanosized vorinostat and bortezomib zein polymeric nanoparticles have been prepared by phase separation method that demonstrated controlled pH-dependent release in respective in vitro dissolution media. Besides this, polymeric nanoparticles showed higher cellular uptake, remarkable cytotoxicity with apoptosis. The drug-loaded nanoparticles exhibited towering anti-migration effect and pro-apoptotic protein induction, which confirmed the overall effectiveness of prepared polymeric nanoparticles in prostate cancer treatment. Owing to minimal toxicity and enhanced in vivo antitumor effects, it opened up a new vista for quality and effective prostate cancer treatment (Thapa et al. 2017). Therefore, pH-responsive polymeric carriers may be a suitable alternative that could assist in the release of anticancer agents at prostate cancer tumor/targeted site.

16.5.2 Enzyme-Responsive Polymeric Nanoparticles

The engineering of poorly soluble small anti-cancer molecules in polymeric prodrug form has grown into extremely promising themes in androgen-independent prostate cancer management. Yuan et al. synthesized the esterase-sensitive galectin 3 binding peptide-mediated esterase-sensitive tumor-targeting polymeric prodrug of camptothecin using camptothecin, oligo (ethylene glycol) monomethyl ether methacrylate for the treatment of prostate cancer. Briefly, in oligo (ethylene glycol) monomethyl ether methacrylate -co- camptothecin -co- galectin 3 binding peptide, camptothecin was linked using a β-thioester bond (i.e. esterase responsive bond). The obtained polymeric nanoparticle showed ~77% camptothecin release (24 h) in the presence of esterase and about 20% cumulative camptothecin (within 24 h) in absence of esterase. Esterase offered the hydrolysis of the β-thioester bond and released the camptothecin from the polymeric nanoparticles. Besides, attachment between polymers to galectin 3 binding peptides performed a pivotal role in boosting cytotoxicity by actually targeting the galectin-3 receptor. The multifunctional polymeric nanoparticles of camptothecin reported better aqueous solubility, remarkable stability, greater intracellular penetration, and increased cytotoxicity in DU145 cells in vitro as compared to native camptothecin. Due to the enhanced permeability and retention effect and galectin 3 binding peptide-mediated tumor targeting, it showed superior anticancer efficacy and diminished in vivo toxicity. The study illustrated that in the management of androgen-independent prostate cancer, polymeric nanoparticles of camptothecin may be an impressive polymeric prodrug (Yuan et al. 2020).

Literature reported that cabazitaxel is a novel inhibitor for the treatment of metastatic castration-resistant prostate cancer. It is a 2nd generation, highly promising taxane compound. Unfortunately, it had solubility and targetability issues which restricted its therapeutic uses. Barve et al. developed the enzyme responsive cabazitaxel polymeric-micelle using 2-[3-(1,3-dicarboxypropyl)ureido]pentanedioic acid (i.e. targeting ligand) and cabazitaxel for successful prostate cancer treatment. In the micelle formulation, enzyme responsive 2-[3-(1,3-dicarboxypropyl)ureido]pentanedioic acid was cleavable due to the presence of the matrix metalloproteinase-2 enzyme. Generally, matrix metalloproteinase-2 is overexpressed in the prostate cancer tumor microenvironment which may favor the design of enzyme responsive drug delivery systems. Fascinatingly, micelle demonstrated very low critical micelle concentration, high entrapment, and drug loading ability. Furthermore, it exhibited enzyme-dependent release of cabazitaxel from polymeric micelle due to the cleavage of the 2-[3-(1,3-dicarboxypropyl)ureido]pentanedioic acid bond. Remarkably, polymeric micelle furnished remarkable cellular uptake of cabazitaxel in prostate cancer than the free cabazitaxel molecules. Hence, polymeric micelle showed exceptional tumor growth inhibition ability in mice than the free as well as a plain micelle. Therefore, cabazitaxel polymeric micelle may be a potential substitute for advanced prostate cancer therapy (Barve et al. 2020). Concisely, an enzyme responsive architectured polymeric nanoplatform would be an outstanding class of drug delivery carrier for stimuli-responsive delivery of anticancer molecules.

16.5.3 Ultrasound-Triggered Polymeric Nanoparticles

Literature reports claimed the fact that ultrasound has demonstrated notable impacts in enhancing the delivery of cancer therapy in conjunction with microbubbles. In 2020, Fagerland and colleagues reported the preparation of cabazitaxel-loaded nanoparticles using PEGylated poly[2-ethyl-butyl cyanoacrylate known as cabazitaxel –poly (ethylene glycol)- poly[2-ethyl-butyl cyanoacrylate nanoparticles using the miniemulsion polymerization method. Herein, prepared nanoparticles were used with microbubbles and ultrasound to reduce the tumor size and prostate volume in the preferred transgenic adenocarcinoma of the mouse prostate model. The intravenous administration of prepared nanoparticles resulted in the accumulation of cabazitaxel in the spleen and liver as compared to pure cabazitaxel. Unfortunately, the application of ultrasound and microbubbles combination with nanoparticles did not exhibit any significant difference in overall therapeutic performance including histology grading or proliferation (Fagerland et al. 2020). Therefore, in the future, the optimization of ultrasound quality attributes may assist to improve the entire presentation of anticancer ultrasound-triggered therapy.

16.5.4 Dual-Responsive Polymeric Platforms

The rise in cancer stem cells is directly associated with chemoresistance, which stymies prosperous chemotherapy. Synergistic treatments (a combination of anticancer agents) for both bulk tumor cells and cancer stem cells have proven effective to reverse chemoresistance and treat prostate cancer. In recent attempts, Lin and co-researchers developed the dual responsive (pH and enzyme sensitive) polymeric nanocarrier for docetaxel and rubone (miR-34 activator gene) to the cancer stem cells targeting and taxane resistant prostate cancer treatment. They prepared docetaxel-loaded rubone prodrug micelle by encapsulating docetaxel into poly (diisopropylaminoethanol) (i.e. pH-responsive) and rubone prodrug conjugate with polycarbonate (i.e. glutathione responsive). Herein, the prepared micelle demonstrated remarkable stability and offered to target ability by the enhanced permeability and retention effect. Furthermore, micelle underwent disassembly/expansion due to the poly (diisopropylaminoethanol) protonation. Moreover, glutathione-induced disulfide bond cleavage in the acidic microenvironment of endocytic vesicles. Owing to this, it resulted in the rapid release of rubone and docetaxel into the cytoplasm of prostate cells. Finally, rubone up-regulated the miR-34a gene and accordingly increased the sensitivity of tumor cells towards the docetaxel. The distribution of several other lipophilic anticancer drugs for prostate cancer management can be accomplished by using this dual-sensitive approach (Lin et al. 2019). Overall, owing to its ability to boost the bioavailability of drugs in the prostate cancer tumor area, the resulting stimulation-responsive architectured polymer-centered nanocarriers have been extremely effective in prostate cancer management. Advances in endogenous and exogenous stimuli-responsive architectured polymeric nanoplatforms targeted treatments of prostate cancer have been summarized in Table 16.2.

Table 16.2 Stimuli-responsive architectured polymeric nanoplatforms targeted treatment of prostate cancer

16.6 Advances in Polymeric Nanoparticles for Prostate Cancer

16.6.1 Polymer-Based Superparamagnetic Nanoparticles

Recently, nanoscopic therapeutic systems integrating therapeutic agents, molecular targeting, and imaging functionality have taken on a growing dynamism and demonstrated considerable therapeutic prospects. Multifunctional polymeric nanoparticles have been prepared by Fang et al., which offered remarkable merits including controlled release of docetaxel, efficient magnetic resonance imaging contrast properties, and prostate cancer target abilities, etc. Briefly, docetaxel and superparamagnetic iron oxide were encapsulated into the shell of targeted nanoparticles, which were composed of poly (lactic-co-glycolic acid), poly (ethylene glycol), and Wy5a-aptamer. Herein, polymeric nanoplatforms helped in the controlled release of docetaxel from polymeric nanoparticles. Additionally, it boosted the contrast-enhanced aptitude. The incorporation of Wy5a-aptamer has demonstrated the targeted delivery of actives to prostate cancer cells. Furthermore, in vivo experiments confirmed the noticeable antitumor magnetic resonance imaging ability with significantly lowering systemic toxicity. Hence, in the future, this multifunctional polymeric Wy5a-aptamer functionalized docetaxel-loaded superparamagnetic iron oxide-based polymeric nanoparticles can be preferred as an efficacious therapy for castration-resistant prostate cancer management (Fang et al. 2020).

To address systemic chemotherapy barriers, various vehicles have been created to encapsulate and distribute anticancer molecules, viz. dendrimers, polymeric nanoparticles, micelle, etc. One of the key drawbacks of such vehicles is that drug delivery and progression of treatment cannot be tracked in real-time. Awareness of the biodistribution of an anticancer molecule is essential for prostate cancer targeted application. Concisely, for the design of comprehensive substitute cancer therapies, i.e. drug carriers, which can also act as tracers and contrast reagents, are essential. Theranostic magnetic nanoparticles that simulcast both imaging agents and therapeutic agents are of significant meaning for the treatment of prostate cancer. In 2013, Wadajkar and co-authors developed the thermoresponsive polyarginine peptide modified poly[N-isopropylacrylamide-acrylamide-allylamine] magnetic nanoparticles using poly[N-isopropylacrylamide-acrylamide-allylamine] coated superparamagnetic nanoparticles followed by conjugation of prostate cancer-specific peptide for active targeting of prostate cancer tumors. Poly [N-isopropylacrylamide-acrylamide-allylamine] has a 40 °C critical solution temperature that provides thermo-responsive behaviors in the formulated nanoparticles. Additionally, it offers the amine functionalities for bioconjugation in nanoparticles. Further, prepared nanoparticles exhibited excellent superparamagnetic behavior before and after the conjugation of peptide (i.e. R11). It also demonstrated the remarkable biocompatibility with normal prostate cells up to 500 mg/mL concentration of nanoparticles. The cellular uptake by PC3 and LNCaP cells was found to be dose-dependent and showed more distribution in prostate cancer tumors. Herein, bioconjugation of magnetic nanoparticles declined (30%) the magnetic resonance in tumors as compared to plain poly [N-isopropylacrylamide-acrylamide-allylamine] magnetic nanoparticles (0%). In conclusion, the application of prepared nanoparticles offered a potential platform for targeting and monitoring prostate cancer, i.e. therapeutic and diagnostic applications (Wadajkar et al. 2013).

Eupatorin (flavonoid) showed anticancer activity, but had poor aqueous solubility, and accordingly low bioavailability. The rapid degradation of eupatorin limited its efficacy. In this pioneered work, the poly (ethylene glycol) methyl ether-block- poly lactic-co-glycolic acid @ iron oxide nanoparticles were used as a possible nanocarrier for delivery of eupatorin to DU-145 and LNCaP human prostate cancer cells. In brief, nanoparticles have been prepared by the nanoprecipitation method. The obtained nanoparticles demonstrated initial burst release in 24 h (30%) and further sustained the eupatorin release up to 200 h. Herein, coated superparamagnetic iron nanoparticles with poly (ethylene glycol) methyl ether-block- poly (lactic-co-glycolic acid) provided superior biocompatibility and increased the uptake by prostate cancer cells. The increased apoptosis and necrosis rate decline claimed that the eupatorin encapsulation in poly (ethylene glycol) methyl ether-block- poly lactic-co-glycolic acid-coated iron oxide nanoparticles accomplished the enrichment in anticancer activity in DU-145 and LNCaP human prostate cancer cell lines than the pure form of eupatorin. Hence, eupatorin encapsulated nanoparticles can be preferred as a suitable surrogate for pharmacological applications (Tousi et al. 2020).

In another study, Nagesh and colleagues have illustrated prostate-specific membrane antigen targeted cyclodextrin, pluronic F127 coated docetaxel-loaded superparamagnetic polymer-coated nanoparticles for prostate cancer treatment. In brief, cyclodextrin coating in prepared nanoparticles offered the hydrophobic cavity for the physical entrapment of hydrophobic anticancer molecules (docetaxel), whereas the coated pluronic polymeric chains offered the stability of the nanoparticles in suspension. These nanoparticles demonstrated efficient internalization of prostate cancer cells. Additionally, prostate cancer cells demonstrated the down-regulation of anti-apoptotic proteins, induction of the expression of apoptosis-associated proteins, inhibition of chemo-resistance associated protein, etc., which confirmed the anticancer potential of docetaxel loaded superparamagnetic polymeric nanoparticles. Therefore, the preparation could be appropriate for prostate cancer-targeted treatment (Nagesh et al. 2016).

The combined effect of chemotherapy and photothermal treatment provided a more accurate supply of active in the nanosystem. The literature claimed that the photothermal agents are majorly preferred for cancer thermal therapy, in which near-infrared light converts into cytotoxic heat. Owing to the astonishing properties of selenium nanoparticles including biocompatibility, anticancer efficacy, minimal toxicity, etc, it is gaining much attention from the researchers as a possible mediator and drug carrier for anticancer therapy. In 2020, Liu and co-authors reported doxorubicin incorporated poly (ethylene glycol) functionalized copper and selenium nanoparticles for prostate cancer treatment. Briefly, the hydrophilic nature of doxorubicin conjugated nanoparticles has been increased by polyethylene glycol-2000 linking on the surface of the nanoparticles that offered the admirable solubility for nanoparticles. They mentioned that near-infrared achievable selenium nanoparticles provided the heat energy which resulted in the release of encapsulated doxorubicin from polymeric nanoparticles. Further, functionalized nanoparticles offered high cellular uptake ability, superior cytotoxicity against DU145 and LNCaP cells. The prepared nanoparticles of red blood cells biocompatibility showed the dose relied on the hemolytic effect that confirmed the reduction in toxicity of the polyethylene-based nanoparticles and without poly (ethylene glycol) nanoparticles (water as positive control). Based on findings, it was stated that the functionalized nanoparticles exhibited insignificant hemolysis, which accordingly confirmed the biocompatibility of prepared nanoparticles (Liu et al. 2020).

16.6.2 Polymeric Nanoparticles Bearing Radionuclide, Magnetic Resonance Imaging Agents and Metal Nanoparticles

An abundance of research has shown that there is no successful method of treating androgen-resistant prostate cancer lethality. In 2019, Wang et al. designed the multifunctional paclitaxel-loaded pluronic- polyethyleneimine gold nanoparticles for androgen-resistant prostate cancer treatment by incorporating organic and inorganic material with gold nanoparticles using the film emulsification method. It exploited the usage of gold nanoparticles that offered photodynamic effects, photothermal effects, chemotherapy, etc. effects. In brief, pluronic- polyethyleneimine nanoparticles helped to develop micelles, which encapsulated paclitaxel. Paclitaxel helped to arrest the prostate cancer tumor cell cycle, whereas nanoparticles demonstrated the controlled release of paclitaxel, TRPV6 cation channel blocking, amplifying the cell cycle arrest. Increasing the temperature and producing reactive oxygen species offered improved cellular toxicity as well as apoptosis. It also enhanced the tumor targeting and achieved low toxicity in liver function in androgen resistant prostate cancer treatment followed by minimal side effects to other normal body organs. Final nanoparticles offered a detailed, productive, and broad strategy for deadly androgen-resistant prostate cancer as a particular synergistic framework combining several therapeutic protocols with negative toxicity (Wang et al. 2019). “All in one” technologies should be designed for targeted, bio-consistent, and synergistic merits to battle the heterogeneity of cancer.

In 2019, Poudel et al. designed the docetaxel-coated copper sulfide nanoparticles followed by wrapping of lanreotide linked poly (ethylene glycol)-di-stearoyl phosphatidylethanolamine platform, which offered targeted delivery of docetaxel with prolonged circulation time by avoiding unwanted docetaxel release. After near-infrared irradiation, a photothermal carrier assisted in the release of docetaxel from nanoparticles to the targeted site in a regulated manner. Furthermore, compared to the non-targeted polymeric platform and free/plain anticancer drugs, the induction of apoptotic markers increased tumor aggregation and maximized growth inhibition of the tumor. Therefore, owing to the excellent results of this study, it may offer futuristic applications for promising prostate cancer treatment (Poudel et al. 2019).

Bulmahn et al. developed the multifunctional hierarchical nano-formulation using chitosan-coated poly (lactic-co-glycolic acid) loaded with docetaxel and interleukin-8 and small interfering RNA was bound with upconversion nanoparticles (upconversion nanoparticles) through electrostatic force for castration-resistant prostate cancer treatment. Fascinatingly, this theranostic of prepared nanoparticles offered concurrent gene therapy and chemotherapy along with image-guided combination therapy using bimodal optical and magnetic resonance imaging agents in combination. Furthermore, this novel multifunctional hierarchical nanoformulation accomplished a dramatic reduction (p < 0.001) in IC₅₀ in preferred PC-3 cells than the free form of docetaxel. Owing to the enhanced anticancer potential, it could be preferred as an image-guided combination therapy for castration-resistant prostate cancer management (Bulmahn et al. 2020). Menon et al. designed the nanosized, stable 8-dibenzothiophen- 4-yl-2-morpholin-4-yl-chromen-4-one (radiosensitizer) loaded peptide conjugated poly (lactic-co-glycolic acid) i.e. NU7441-R11-PLGA nanoparticles. It provided the prostate cancer-targeted sustained delivery (up to 3 weeks). Interestingly, these prepared polymeric nanoparticles exhibited biphasic release of radiosensitizer. The cellular uptake of PC 3 cells relied on the dose and magnetic field. In vitro study claimed that the 8-dibenzothiophen- 4-yl-2-morpholin-4-yl-chromen-4-one exhibited an effective radiation sensitizer in prostate cancer cell lines. The combination of poly (lactic-co-glycolic acid) with peptides, which contains 8-dibenzothiophen- 4-yl-2-morpholin-4-yl-chromen-4-one and an appropriate imaging agent will thus help to monitor, target, and image nanoparticles and effectively radiosensitive prostate cancer cells (Menon et al. 2015).

16.6.3 Miscellaneous Advanced Polymeric Platform

Conventional approaches to cancer care are suffering from several drawbacks, such as non-selective differentiation toward healthy cells and cancer cells. Regarding this, in 2020, Changizi et al. designed folic acid conjugated polymeric gold nanoparticles for the active targeting of prostate cancer cells. These prepared nanoparticles offered real-time fluorescence as compared to non-targeted polymeric gold nanoparticles (p < 0.001) and along with that it induced radiosensitivity in LNCaP prostate cancer cells. The polymeric gold nanoparticles uptake was significantly (p < 0.01) raised in prostate cancer cells as compared to normal cells owing to folic acid conjugation on the surface of nanoparticles. Furthermore, prostate cancer cells showed a higher cytotoxic effect because of the presence of folate receptors on the surface of prostate cancer cells. Finally, these nanoparticles and ionizing radiation showed a significant synergistic dose-dependent effect (p < 0.01) on the induction of apoptosis and necrosis of cells. Concisely, obtained nanoparticles lead to several merits (higher and specific cellular uptake/accumulation) that reserved a room as a radio-sensitizer for futuristic anticancer applications (Changizi et al. 2020).

In another study, Guo et al. prepared the gold nanoparticles-poly (ethylene glycol) transferrin targeting ligand (negative charge) and gold nanoparticles polyethyleneimine- folic acid (positive charge) for small interfering ribonucleic acid delivery. Small interfering RNA was attached to the surface of modified folic acid nanoparticles via electrostatic forces. Herein, the surface-modified gold nanoparticles resulted in lower cytotoxicity in prostate cancer cells. Furthermore, gold nanoparticles poly (ethylene glycol) with the transferrin targeting ligands demonstrated receptor-mediated nanoparticles uptake in PC3 cells that confirmed the transferring targeting ligands receptors in prostate cancer cells. On the other hand, folate-receptor targeting ligands with gold nanoparticles-polyethyleneimine offered small interference ribonucleic acid delivery in LNCaP cells. Overall, both these nanoparticles can be a suitable substitute for small interference ribonucleic acid delivery in prostate cancer therapy (Guo et al. 2016). Therefore, polymeric nanoparticles are successful candidates for combined cancer therapy as vehicles for pharmaceutical products or molecules. They deliver remarkable advantages in terms of stability, biocompatibility, biodegradability, adaptability, contrary to inorganic nanoparticulate systems. Overall, polymeric nanoparticles containing revolutionary polymers that respond to specific microenvironmental tumor conditions including reduced pH, high levels of reactive oxygen species, overexpressed enzymes, etc. may be used to activate regulated delivery of anticancer drugs. Advances in multifunctional architectured polymeric nanoplatforms targeted treatments of prostate cancer have been summarized in Table 16.3.

Table 16.3 Multifunctional architectured polymeric nanoplatforms targeted treatment of prostate cancer

16.7 Challenges

The recent dramatic increase in the number of polymeric nanostructures approved by the food and drug administration is used in the clinical setup of cancer. Additionally, there are several attempts made to enhance the therapeutic characteristics of anticancer drugs which are already formulated. Interestingly, the polymeric nanoparticles have displayed appreciable bioavailability and regulated biodistribution by utilizing stimuli responding pathways for the release of anticancer drugs in the body. We witness that, including all characteristics as a "magic bullet" for managing prostate cancer and other types of cancers, comprehensive efforts in preclinical and clinical technology are being carried out to create combined therapy. Also, food and drug administration has authorized nearly distinct nanodrugs (primarily polymeric nanoparticles) for prostate cancer and other cancer treatments. The synthesis and use of polymeric nanoparticles have boosted and revolutionized a lot of interest as a personalized medicine option for prostate cancer treatment. The manufacturing of reliable polymeric nanoparticles in the prostate cancer treatment domain is ensured by closer collaboration across academia and industry with the usage of innovative technologies.

The strategic focus is also on the efficient bonding of anticancer drugs to improve drug retention. The theranostic polymeric nanoparticles can be efficiently used for assembling separate nanoparticles for cancer diagnosis, imaging, and simultaneously targeted anticancer drug delivery. In the future, special attention may be provided to the design of theranostic polymeric nanoparticles that can track the prostate cancer stage. These versatile polymeric nanoparticles may be helpful for the early detection and successful treatment of prostate cancer and can be used during the process of prostate cancer stage monitoring. The theranostic polymeric nanoparticles for clinical purposes should have a greater capacity for tissue penetration and greater biosafety parameters with lower cell toxicity. In addition to this, these polymeric nanoparticles can uphold the poorly soluble anticancer molecules that can offer the reasonable retention of anticancer drugs in the prostate cancer tumor cell or tissue microenvironment. Recently, stimuli-responsive polymeric nanoparticles have demonstrated a substantial potential in the delivery of the oral anticancer agent. Therefore, such stimuli-responsive polymeric nanoparticles can be used to design innovative polymeric nanoparticles, which can assist to recognize genetic mutation, epigenetic changes, and deoxyribonucleic acid mismatch. Additionally, it can be designed to deliver anticancer molecules in the prostate cancer tumor and release the drug at various stages of prostate cancer.

Despite the plentiful advantages of polymeric nanoparticles, the biocompatibility and biodegradation of polymeric nanoparticles is still a big concern for study and development. The design and development of polymeric nanoparticles have also resulted in solving the problem of biotoxicity i.e. nanotoxicity and biodegradability. In the event of nanotoxicity, the polymeric nanoparticles' shape, particle size, and uniformity of nanoparticles should be better managed. In the case of biodegradability, nanoparticles should be fully broken down and removed from the patient's body following the release of the payload. Besides, to resolve such a major issue, several biodegradable polymers (viz. chitosan, poly (lactic-co-glycolic acid), polylactide, etc.) can be preferred as a potential substitute for targeted prostate cancer therapy. Besides this, appropriate polymerization can be preferred to synthesize biocompatible polymeric nanoparticles. Interestingly, polymeric nanoparticles displayed controlled release of the anticancer agent; therefore, it can be preferred as a better alternative for the intravenous route. In a future point of view, theranostic polymeric nanoparticles can be potentially approved as personalized medicines in prostate cancer, in which the nature of these nanoparticles may be tailored to improve diagnostic or therapeutic outcomes by factors viz. patient age, prostate cancer stage, etc. Also, polymeric nanoparticles can be synthesized and filled with immunologic cell mortality initiating agents to promote prostate cancer tumor cell deaths. Additionally, the area of interest will be polymeric nanoparticles including complex features and multifunctional attributes (i.e. theranostic nanosystems), but with a simple design.

16.8 Conclusion

Concisely, prostate cancer is a multifaceted male reproductive system-related frequent non-skin cancer type that necessitates being dealt with successfully on many fronts. The biological complexity and diversity of prostate cancer are still limiting steps for scientific advancement. Fascinatingly, the efficacy of anticancer agent-loaded polymeric nanoparticles has greatly improved in chemotherapy as demonstrated by abundant preclinical/clinical findings. Accordingly, various tactics for attempting to change the physiochemical attributes of polymeric nanoparticles are possible, which are accurately loaded with various approved chemotherapeutics and further targeted to prostate cancer cells/tissue. Out of reported techniques, stimuli-responsive drug delivery demonstrates excellent therapeutic action. In that, two different anticancer molecules can be delivered to the prostate cancer cells/tissues using several signaling mechanisms in a prostate cancer tumor, which furnishes the synergistic output (known as synergistic therapy) for the prostate cancer treatment. Other pioneering studies reported that the anticancer-loaded/functionalized polymeric nanoparticles showed noteworthy thermionic emission. Therefore, it destroys the prostate cancer tumor cells by boosting the local temperature of the prostate cancer tumor microenvironment, which improves the release of anticancer drugs. Overall, architectured polymeric nanoparticles are providing revolutionary platforms for efficient prostate cancer treatment at different stages followed by remarkable advantages as compared to other nanocarriers. In the future, to confirm the prediction and reliable pharmacokinetics of anticancer drugs for humans, the in vitro and/or in vivo models for the assessment needs to be improved.