Hybrid lipid-polymer nanoplatform: A systematic review for targeted colorectal cancer therapy

Abstract

Colorectal cancer (CRC) is among the most rampant diseases globally and still has a high fatality and relapse rate despite the significant developments in conventional treatment modalities. In the realm of effective cancer treatments, nanotechnology-based drug delivery systems have attracted great interest. The most researched drug delivery system for successful cancer therapy is liposomes because of their unique qualities, such as biocompatibility, improved entrapment efficiency, and scalability as well as cost-effective process. While on the contrary, polymeric nanoparticles possess good stability, controlled release, and the capability for several chemical alterations. However, lipid peroxidation, burst release, restricted surface changes, and polymer toxicity limit their applications. Thus, lipid-polymer hybrid nanoparticles (LPHNPs) have been identified as promising nanosystems with respect to a number of biomedical applications. These particles are a prospective delivery system made up of combinatorial properties of liposomes and polymeric nanoparticles. A deeper understanding of LPHNPs types, synthesis aspects with their controllable parameters, release mechanisms, and surface functionalization are all elements of the current review. This review article emphasizes the significant uses of LPHNPs relating to the delivery of drugs and their targeting as well as the obstacles hampering their clinical translation with the potential for utilizing these nanoplatforms to treat colorectal cancer.

Introduction

Colorectal cancer (CRC) is among the malignancies with the highest global prevalence, since approximately one to two million new cases are identified each year. According to National Cancer Institute, almost 715,000 deaths each year, makes CRC the second most frequently occurring cancer and the fourth most typical factor in cancer-related fatalities which exceeds only by breast, prostate, and lung cancers, thus crossing 1 million population being affected globally. It ranks third amongst males (10 %) and second among women (9.2 %), depending on gender [1]. The anticipated incidence of CRC in the United States of America as of 2022 is around 151,000 cases in adults [2]. The development of appropriate treatment strategies for CRC patients is still very difficult for many oncologists and specialized surgeons. This is due to the fact that the majority of the patient population diagnosed with CRC comes under the geriatric age group [3], [4], [5], [6]. Such elderly patients may have associated comorbidities and hence requires an individualized treatment regimen in most cases [5]. Thus, selecting the right treatment is very crucial which might improve the survival chances. Nonetheless, it is a major risk in today’s medical era that affects every stratum of the population at large. Chemotherapy, radiation therapy, and surgery are the three main therapeutic modalities used today to treat cancer [7], [8], [9]. Apart from this, other methods for managing cancer include the use of a variety of cytotoxic drug classes [10], [11], hormone therapy [12], [13], targeted therapy [14], [15], and immunotherapy [16], [17]. Surgery is typically advised while the disease is still in its early stages and is most successful when all cancer cells can be removed [7]. Although it is primarily used to debulk tumours and enhance the quality of life, it is also employed in later stages. Therefore, the most frequently employed methods for the treatment of cancer are chemotherapy and radiation [18], [19], [20].

Chemotherapy and radiation, in contrast to surgery, often never entirely cure the disease and are typically only able to destroy a small percentage of tumour cells with each treatment programme [18]. In chemotherapy, cytotoxic anticancer medicines are generally utilised to kill metabolically active cancer cells. Since most healthy cells don't divide as frequently as cancer cells do, these cytotoxic medications have a proportionately smaller impact on them. The lack of tumour selectivity in these treatments, however, means that even when they are used to prolong or improve the patient's quality of life, they frequently have serious adverse effects related to systemic toxicity [21]. Similarly, radiation therapy also harms healthy tissues, cells, and organs giving rise to “mucositis”, a major adversarial condition [22], [23], [24], [25], [26]. This in a way limits the tolerance ability towards chemotherapeutic agents along with compromised nutritional status in cancer patients. Furthermore, multidrug resistance syndrome (MDRS) is one of the main reasons why cancer treatments fail, which is typically acquired after repeated chemotherapy exposure [27], [28], [29]. The MDRS phenomenon is characterized by the efflux of anticancer drugs through some molecular pumps of the cancer cells resulting in reduced therapeutic effect [30], [31]. Thus, because of the challenges such as tumor-specific delivery, appropriate loading into the delivery vehicle, stability of the formulation, and concomitant risk of toxicity to the adjacent normal cells, selecting the best possible delivery vector or system is crucial in order to effectively treat cancer. The optimum drug delivery system (DDS) selected should provide maximum advantage and minimize the limitations of the carefully chosen class of anticancer agents [32], [33].

The utilisation of multiple designed nanoparticles (NPs) for controlled drug delivery is the foundation of nanotechnology, a potential platform for drug delivery to tumor cells. The diameter of the NPs ranges from 1 to 1000 nm [27]. Compared to current anti-cancer therapies, NPs' distinctive physiochemical characteristics, for example, dimension, morphology, and surface properties like area and charge, are advantageous [35], [36]. These traits have been noted by researchers investigating studies related to cancer treatments and diagnostic applications. Hydrophobic chemotherapeutics are more bioavailable because of these NPs' improved aqueous solubility, increased in vivo circulation time, and site-specific therapeutic cargo delivery by preventing non-tumor-specific drug buildup in healthy tissues. For the prevention, diagnosis, and therapy of cancer, NPs represent an appealing drug delivery vehicle due to their high payload and efficient DDS. Liposomes, micelles, solid lipid NPs, lipid nanodiscs, nanocubosomes, lipid NPs derived from plants, polymers, and inorganic NPs are just a few of the many adaptable NP-based systems that are employed to transport drugs, certain genetic materials, peptides, proteins, and imaging agents to the location of the tumor.

In order to investigate the therapeutic effectiveness in metastatic CRC expressing epidermal growth factor receptor (EGFR), M. Garrodo et al. [30] prepared oxaliplatin and cetuximab loaded liposomes. The formulation showed superior drug accumulation with a 3-fold high level in comparison to non-targeted preparation. In another study by Yang et al. [31], citric acid coated magnetic nanoparticles and doxorubicin were together loaded in liposomes. They found that the nanocarrier exhibited no cytotoxicity with approximately 56 % of cell death evaluated against the CRC cell line i.e. Murine Colon Tumor 26 (CT-26). Despite these benefits, the practical usage of traditional liposomes was disappointing. Their propensity to form aggregates, which causes an early release profile and prompt elimination from the systemic circulation by the mononuclear phagocyte system (MPS), makes their in vivo stability a problematic situation for researchers. However, these limitations can be overcome by designing long circulating liposomes via conjugating the phospholipid with polyethylene glycol (PEG) by a process known as PEGylation [39], [40]. This technique is particularly helpful for improving liposomal stability, decreasing interactions between liposomes and plasma proteins, and lengthening the average circulation duration of liposomes [34]. However, the PEGylated stealth liposomes have a drawback that PEG attachment prevents the liposomes from being taken up by cells and frequently prevents them from eluding endosomal trapping, which might result in a major loss of DDS function [35]. This severely restricts their capacity to deliver low-dosage therapies like small interfering ribonucleic acid (siRNAs) or protein molecules.

A cationic PEG-lipid micelle's siRNA delivery effectiveness was studied by Y. Lu et al [36]. By adding a cationic lipid 1,2-Dioleoyl-3-trimethylammonium propane (DOTAP) to a methoxy-poly(ethylene glycol)-poly(ɛ-caprolactone) copolymer, the investigators formulated (mPEG-PCL) micelle, which they then loaded with myeloid leukemia 1 (siMcl1) or B-cell lymphoma-extra large (siBcl-xl). The effectiveness of the produced siMcl1/mPEG-PCL or siBcl-xl/mPEG-PCL micelle complexes was evaluated in a mouse CRC model. Mice with xenografted colon tumors were well inhibited by intra-tumoral injection of micelle complexes, indicating that this altered lipidic micelle may be a powerful DDS for delivering gene therapies in treating colon cancer. In one of the studies, E. Kimura et al. [37] nanoencapsulated Hypericin with Pluronic 123 micelles. They investigated the micelles’ cytotoxic capacity against Caco-2 (Cancer coli-2) and HT-29 (Human Colorectal Adenocarcinoma Cell Line) intestinal colon tumor cells. The molecule had a notable ability to penetrate the membrane, which caused cell death. Low drug loading efficiency, poor physical stability in vivo, and insufficient cellular contact of micelles with malignant cells are all disadvantages of micelles. Additionally, they are also less capable to load drugs than liposomes. T. Smith et al. [38] in their study, prepared solid lipid NPs (SLN) loaded with 5-Fluorouracil (5-FU) and examined the effects against CRC. The tumor growth was greatly slowed down by the SLN, which had a 263 nm particle size and entrapment efficiency of 81 %. The research work done by K. Kamel et al. [39] showed the coating of SLNs with chitosan for nutraceutical and 5-FU encapsulation. When tested on HCT-116 (Human Colorectal Carcinoma) cell line, the formulation was able to significantly reduce tumor growth. Despite the several advantages of SLNs, they still have the drawback such as inadequate encapsulation of hydrophilic pharmaceuticals, which diffuse inefficiently in the melting lipid component and exhibit poor loading capacity during the synthesis.

R. Kuai and colleagues [40] recently created a unique high-density lipoprotein (HDL)-imitating nanodisc incorporating doxorubicin. The immune checkpoint blockage was enhanced by the nanodisc in a CRC murine model. Doxorubicin was delivered using HDL-nanodiscs, which caused immunogenic cell death. There were no adverse effects on CRC cells. Strong antitumor cluster of differentiation 8 (CD8 + ) T cell responses were induced by the injection of nanodiscs, expanding T cell epitope recognition. This study provides compelling proof that nanodisc-based chemotherapy can activate antitumor immunity and make cancers susceptible to immune checkpoint inhibition. Though nanodiscs have a lot of potential, they also have significant limitations, like, the inability to control size and instability at low pH levels. Recently, Y. Almoshari et al. [41] developed dual anticancer agents (curcumin and temozolomide) loaded nanocubosomes. Using HCT-116 colon tumor cells, the antitumor effectiveness and apoptosis were assessed. The smaller particle size was found to promote more cellular absorption and cell death. According to another study reported, nanocubosomes containing either cisplatin alone or a cisplatin-metformin combination were developed by M.M. Saber et al. [42] using an emulsification process. When compared with free cisplatin, the prepared cubosomes had more potent cytotoxic effects on CRC cells (HCT-116). The nanoparticles were able to cause apoptosis by disrupting numerous metabolic pathways, depleting glucose, and lowering energy levels. However, large-scale production might be challenging occasionally due to excessive viscosity. Major research focussing on the development of nanotherapeutics for CRC treatment includes some of the commercialized examples like Camptostar®, Eloxatin®, Avastin®, Opdivo®, Yervoy®, Lonsurf®, Vectibix®, and Keytruda®.

A new class of lipidic nanocarriers, lipid-polymer hybrid nanocarrier system, has arisen in the field of CRC treatment in order to circumvent the constraints imposed by traditional and diverse nano-based delivery systems [43]. Widely investigated conventional delivery systems for the treatment of CRC are liposomes and polymeric NPs with their specific advantages and disadvantages as discussed in the section below. Furthermore, various literature has brought to light the potential of hydrogels, polymer network-based formulations, and other lipid-based nanoplatforms for the diagnosis, treatment, and management of colorectal cancer [44], [45], [46]. However, the reported review analysis, scientific progress, and our research entail the potential of hybrid nanoplatforms as a favourable carrier system for the better management of CRC. Also, the hybrid core–shell nanoplatforms offer several advantages such as improved drug loading due to active and passive targeting capabilities, altered release mechanisms, increased biological half-lives, and protection of the active pharmaceutical ingredient (API) in harsh environments [47]. To the best of our knowledge so far, no literature has been reported that discusses the important applicability of lipid-polymer hybrid nanoparticles (LPHNPs) in CRC treatment. Hence, the present review article emphasizes various forms of lipid-polymer hybrid nanocarrier systems, their manufacturing process, and the formulation characteristics that need to be regulated for CRC-related applications. Additionally, the most noteworthy and recent investigations and applications of hybrid lipid-polymer systems as targeted tumor therapies in this area have been comprehensively focused on.