Recent development of aptamer conjugated chitosan nanoparticles as cancer therapeutics

https://doi.org/10.1016/j.ijpharm.2022.121751Get rights and content

Abstract

There is a surge in demand for safe and targeted therapy against cancer as the conventional treatment approach fails to reach the specific site. Chemotherapeutic agents are generally associated with low tumoral accumulation, off-site effect, and drug resistance. Targeted delivery with the use of nanocarrier could elevate the drug accumulation at the target site, reduce toxicity to non-cancerous cells, overcome drug resistance, and reduce dosing. Aptamers are single-stranded oligonucleotide that folds in a way to get into the pocket of target cells with high affinity and specificity due to the ability to recognize and interact with the biomarkers such as nucleolin, Mucin, EGFR, etc. overexpressed by cancer cells. Aptamer also plays a key role in cancer immunotherapy and the delivery of anti-cancer agents. The review brings the light upon the use of aptamer-chitosan nanoparticles against cancer therapy and their role in the reduction of toxic effects.

Introduction

Chemotherapy has remained in forefront of cancer treatment. Despite of such fact, cancer acquires the highest rank among the principal causes of death around the world (Mukherjee et al., 2019). A major reason is chemotherapy or radiotherapy usually lacks the specificity towards cancer neovasculature that causes severe toxicity among cancer patients (Chadar et al., 2021b, Choudhury et al., 2019, Choudhury et al., 2017, Gorain et al., 2020, Pandey et al., 2018, Taghdisi et al., 2016, Yazdian-Robati et al., 2016, Zununi Vahed et al., 2019). The patient dies not only due to the severity of the disease but also due to toxic effects on cardiac, hepatic, gastric, or renal cells that hamper their physiological function. Thus, an effective treatment strategy should be adapted that can kill only the tumor cells sparing the normal anatomical structure (Burnett and Rossi, 2012, Zhao et al., 2015).

Nano drug delivery system could be a better approach for delivery of cargos in a more controlled and sustained manner, fitting absolute therapeutic index throughout the desired period with decreased frequency of administration (Danhier et al., 2012, Jain et al., 2018, Kesharwani et al., 2019, Patel et al., 2016, Paul et al., 2021, Sheikh et al., 2021, Tekade et al., 2016). Nanoparticles are believed to accumulate in the neoplastic site due to the leaky vasculature and absence of a suitable lymphatic drainage system (Chadar et al., 2021b, Duncan, 2003, Kaur and Kesharwani, 2021, Kesharwani et al., 2015, Kesharwani et al., 2014, Nitheesh et al., 2021, Singh et al., 2020, Singh and Kesharwani, 2021a). An extended range of polymers have been investigated and studied that could mediate the effective delivery of therapeutic agents towards the desired area. The polymeric nanoparticles (NP) have been studied enormously which showed great benefit in the category of medical applications (Singh et al., 2021, Vaishnav Pavan Kumar et al., 2021). Construction of smart molecules that fit into the model as nanostructures could seize a dramatic effect on the performance of such nanoparticles in deciphering modern biological benefits. Considering and monitoring the safety of the delivery system, biodegradable and non-toxic polymers are majorly focused especially the natural polymer-polysaccharide (Dubey et al., 2021, Lian et al., 2017, Singh and Kesharwani, 2021b, Surekha et al., 2021). It is essential to consider the physicochemical property of the nanoparticles and their influence on cells. The surface potential, shape and size are responsible features that dominate govern cellular uptake and toxicity. The more the positive charge on the surface of nanoparticle, the more is the ability to engage with the cells and hence promote toxicity (Kai et al., 2011). The smaller the size of the particle, the more surface area would be available to interact with the biological components such as carbohydrates, fatty acids and nucleic acids. The small-sized particles are likely to enter the cells conferring cellular damage (Jiang et al., 2008). The shape also confers cellular damage. The rod shaped particles are higher cytotoxic than the sphere shaped nanoparticles (Lee et al., 2014). However, the reason behind such an influence is still under study.

Among them, chitosan was found effective as a colloidal drug carrier owing to its cost-effectiveness, biocompatibility, biodegradability, sustainability, and non-toxic nature (Chadar et al., 2021a, Patnaik et al., 2021, Turon et al., 2017). Chitosan, an alkaline polysaccharide, is deacetylated derivative of chitin, consisting of β-(1 → 4)-linked D-glucosamine and N-acetyl-D-glucosamine units (Shanmuganathan et al., 2019). Maintaining safety is key step for any therapy, which chitosan had effectively exhibited. Tapola et al. in a study ascertained the safety of chitosan after an oral dose of 6.75 g for eight weeks, where no prompted observable effects (level of carotene, vitamins, and other biological effects) were seen (Tapola et al., 2008). Moreover, it was also safe after intravenous injection of chitosan given to rabbits in the range of 7.1 to 8.6 mg/kg/day for 65 days (Kean and Thanou, 2010). Chitosan NPs could be modified in such a way for exhibiting functions towards specific cells; therefore, cell-specific targeting of chitosan NPs in wake of the drug development field can prevent undesired interactions, improve local drug concentration, reduce toxicity and side effects (Mazzotta et al., 2020). Active targeting of nanoparticles can be achieved through surface modification with aptamers, peptides, gene silencing agents like siRNA, miRNA (Sefah et al., 2013, Shangguan et al., 2006) antibodies, etc. (Amer, 2014, Haley and Frenkel, 2008, Morita et al., 2018, Ren et al., 2021b). The modern era for the treatment of cancer experienced the extraordinary benefit of aptamer as targeting ligand to a specific site for cancer therapy and diagnosis.

Aptamers are single-stranded (ss) DNA or RNA oligonucleotide comprising 25–90 nucleotide bases, extracted through the process of SELEX, which fold in such a way to configure into a 3D structure enabling them to bind effectively and efficiently to the cancer biomarker (Cadinoiu et al., 2019, Ray and White, 2010, Sheikh and Kesharwani, 2021). In its contrast, peptide aptamers comprising of only 15–20 amino acids indeed recognize significant molecules and interact with high specificity. Liu and team performed an unbiased screening to optimize a peptide aptamer that can work against SOX2. SOX2 overexpressing has been reported in various malignancies including esophageal squamous cell carcinoma. The results declared that the optimized peptide aptamer (P42) inhibited the growth and metastasis of esophageal cancer cells (Liu et al., 2020) Aptamers are potentially used due to numerous benefits such as non-immunogenicity, excellent tissue permeability, high stability in different environment of pH and organic solvents, ability to characterize and modify, along with high specificity and excellent binding affinity to pockets of various target antigens that allow for their rapid clinical effect (Gao et al., 2019). In contrary to antibodies, the aptamers are not detected as aliens in the human body, which makes them a unique diagnostic and therapeutic agent (Golichenari et al., 2019, Shahdordizadeh et al., 2016).

Thus, using a combined feature of polymeric nanoparticles with a specific targeting agent could provide a promising candidate having a potential of an effective and safe delivery option that could fill the voidness of a novel strategy in the ground of the oncology market. Thus, the present review focused on aptamer grafted chitosan nanoparticles in oncotherapy platform that lay potential in targeting only the tumor cells sparing the physiology of healthy cells, thereby maintaining and increasing the health statistics. It is worth mentioning that previous studies have been done that illustrated the potential of aptamer bounded nanoparticles in cancer therapy (Liu et al., 2022), however, we tried to extract more information on aptamer grafted chitosan nanoparticle in cancer therapy and their conjugation with different kinds of aptamers.

Section snippets

Chitosan and its role in delivery of therapeutic cargos

Chitosan is a natural, cationic polymer originated by the deacetylation of chitin, which is the second commonest polysaccharide following cellulose (Geethakumari et al., 2022, Vikas, 2021). Chitins are mainly restricted to the skin fibre of crustaceans along with the mixture of salts like calcium carbonates and other organic compounds like pigment, proteins and lipids. Therefore, to obtain chitosan, the minerals and other associated compound with chitin have to be removed by deacetylation in

Cellular uptake mechanism of aptamers

The target-based delivery of aptamer into the cancer lesions can be achieved by selective internalization into the cancer cells. The characteristic recycling of selected target and receptor mediated internalization of aptamer towards the selected cells verify the optimal efficacy of targeted ligand. The internalization of aptamer towards cell membrane from the cell surface is enabled through well-defined pathways: phagocytosis, micropinocytosis, and clathrin and caveolae-mediated endocytosis.

Role of aptamer as immunotherapy

There is a surge in demand of safe therapeutic candidates which may prolong the anti-tumor potential and could work in synergy with chemotherapy. Immunotherapy has emerged as a groundbreaking approach in the past few years, specifically in cancer therapy (Rosenberg, 2012, Schumacher and Schreiber, 2015). Current immunotherapeutic approaches can, however, alter the immune system mechanism but, most of such alteration is conveyed with significant immune toxicities. To overcome such issues,

Chemotherapy delivery service of aptamer in cancer therapy

The clinical experts are still reluctant to use chemotherapeutic agents on cancerous patients. The major and foremost reason is high toxicity. The therapy takes more time to help the patient overcome cancer but also hamper the physiological function of normal cells as well. As a result, patients develop gastrointestinal disorders (Cinausero et al., 2017) induced by chemotherapy, peripheral neuropathy (Castel et al., 2017, Zajaczkowską et al., 2019), cardiotoxicity (Avila et al., 2019, Florescu

Target conferring effect of aptamer

Early introduced in 1990, aptamers were defined as the short single-stranded (ss) nucleic acid sequences that expanded their binding to several targets including cells, proteins, metal ions, and other chemical components. Aptamers provide a therapeutic niche in a more similar way to that of monoclonal antibodies, but, in a more pronounced way such as low to no immunogenicity, less batch variation, ease of production, prolong shelf life, renowned stability and targeting potential (Pednekar et

Aptamer conjugated chitosan NP for cancer therapy

A conjugation of aptamer with a drug delivery system provides a new vehicle called targeted drug delivery system (TDDS). Since nanoparticles due to their small charge can encapsulate a sufficient amount of drug and can accumulate at the site of the tumor due to their leaky vasculature. However, the action cannot be mediated to the specific site. This in turn causes toxicity even to normal cells affecting their normal physiology. Aptamers are ssDNA or RNA oligonucleotides that could fix into the

Concluding remark

Aptamers are the exceptional ligands that recognize and bind the target cells with high affinity and specificity. They are considered as a promising candidate in the delivery of chemotherapeutics, genes, and several diagnostics. Despite such promising and well-established results, they still, failed to reach the clinical market. The reason could be rapid filtration and distribution to tissues from the plasma compartment, high nuclease susceptibility which decreases the affinity and

Disclosures

There is no conflict of interest and disclosures associated with the manuscript.

Credit author statement

All the authors have been contributed significantly and equally to complete this manuscript.

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgements

The authors extend their appreciation to the Deputyship for Research & Innovation, Ministry of Education in Saudi Arabia for funding this work through the project number IFPRP-72-166-1442 and King Abdulaziz University, DSR, Jeddah, Saudi Arabia.

References (190)

  • R. Chadar et al.

    Carbon nanotubes as an emerging nanocarrier for the delivery of doxorubicin for improved chemotherapy

    Colloids Surfaces B Biointerfaces

    (2021)
  • H. Choudhury et al.

    Recent advances in TPGS-based nanoparticles of docetaxel for improved chemotherapy

    Int. J. Pharm.

    (2017)
  • H. Choudhury et al.

    Rising horizon in circumventing multidrug resistance in chemotherapy with nanotechnology

    Mater. Sci. Eng. C

    (2019)
  • C.H. Chung et al.

    Nuclease-resistant DNA aptamer on gold nanoparticles for the simultaneous detection of Pb2+ and Hg2+ in human serum

    Biosens. Bioelectron.

    (2013)
  • M. Das et al.

    Multifunctional nanoparticle-EpCAM aptamer bioconjugates: A paradigm for targeted drug delivery and imaging in cancer therapy. Nanomedicine Nanotechnology

    Biol. Med.

    (2015)
  • M. Dash et al.

    Chitosan - A versatile semi-synthetic polymer in biomedical applications

    Prog. Polym. Sci.

    (2011)
  • S. Dehghani et al.

    Self-assembly of an aptamer-decorated chimeric peptide nanocarrier for targeted cancer gene delivery

    Colloids Surfaces B Biointerfaces

    (2021)
  • S.K. Dubey et al.

    Recent advances of dendrimers as multifunctional nano-carriers to combat breast cancer

    Eur. J. Pharm. Sci.

    (2021)
  • M. Ehrlich et al.

    Endocytosis by random initiation and stabilization of clathrin-coated pits

    Cell

    (2004)
  • A. El-Sayed et al.

    Endocytosis of gene delivery vectors: From clathrin-dependent to lipid raft-mediated endocytosis

    Mol. Ther.

    (2013)
  • M. Esfandyari-manesh et al.

    Specific targeting delivery to MUC1 overexpressing tumors by albumin-chitosan nanoparticles conjugated to DNA aptamer

    Int. J. Pharm.

    (2016)
  • N.A. Fonseca et al.

    Nucleolin overexpression in breast cancer cell sub-populations with different stem-like phenotype enables targeted intracellular delivery of synergistic drug combination

    Biomaterials

    (2015)
  • D. Geethakumari et al.

    Folate functionalized chitosan nanoparticles as targeted delivery systems for improved anticancer efficiency of cytarabine in MCF-7 human breast cancer cell lines

    Int. J. Biol. Macromol.

    (2022)
  • Z. Ghasemi et al.

    Aptamer decorated hyaluronan/chitosan nanoparticles for targeted delivery of 5-fluorouracil to MUC1 overexpressing adenocarcinomas

    Carbohydr. Polym.

    (2015)
  • B. Gorain et al.

    Theranostic application of nanoemulsions in chemotherapy

    Drug Discov. Today.

    (2020)
  • X. Guo et al.

    Multi-functionalized chitosan nanoparticles for enhanced chemotherapy in lung cancer

    Carbohydr. Polym.

    (2018)
  • B. Haley et al.

    Nanoparticles for drug delivery in cancer treatment

    Urol. Oncol. Semin. Orig. Investig.

    (2008)
  • B.T. Huang et al.

    A CTLA-4 Antagonizing DNA Aptamer with Antitumor Effect

    Mol. Ther. Nucleic Acids

    (2017)
  • L. Illum

    Nasal drug delivery - Possibilities, problems and solutions

    J. Control. Release

    (2003)
  • A. Jain et al.

    Lycopene loaded whey protein isolate nanoparticles: An innovative endeavor for enhanced bioavailability of lycopene and anti-cancer activity

    Int. J. Pharm.

    (2018)
  • H. Kaur et al.

    Advanced nanomedicine approaches applied for treatment of skin carcinoma

    J. Control. Release

    (2021)
  • T. Kean et al.

    Biodegradation, biodistribution and toxicity of chitosan

    Adv. Drug Deliv. Rev.

    (2010)
  • P. Kesharwani et al.

    PAMAM dendrimers as promising nanocarriers for RNAi therapeutics

    Mater. Today

    (2015)
  • P. Kesharwani et al.

    Dendrimer-entrapped gold nanoparticles as promising nanocarriers for anticancer therapeutics and imaging

    Prog. Mater. Sci.

    (2019)
  • P. Kesharwani et al.

    Dendrimer as nanocarrier for drug delivery

    Prog. Polym. Sci.

    (2014)
  • Z. Khademi et al.

    Co-delivery of doxorubicin and aptamer against Forkhead box M1 using chitosan-gold nanoparticles coated with nucleolin aptamer for synergistic treatment of cancer cells

    Carbohydr. Polym.

    (2020)
  • B.D. Kurmi et al.

    Dual cancer targeting using estrogen functionalized chitosan nanoparticles loaded with doxorubicin-estrone conjugate: A quality by design approach

    Int. J. Biol. Macromol.

    (2020)
  • W.F. Lai et al.

    Design of Polymeric Gene Carriers for Effective Intracellular Delivery

    Trends Biotechnol.

    (2018)
  • W.Y. Lai et al.

    A Novel PD-L1-targeting Antagonistic DNA Aptamer With Antitumor Effects

    Mol. Ther. Nucleic Acids

    (2016)
  • G.Y. Liou

    CD133 as a Regulator of Cancer Metastasis through the Cancer Stem Cells

    Int. J. Biochem. Cell Biol.

    (2019)
  • K. Liu et al.

    Targeting SOX2 Protein with Peptide Aptamers for Therapeutic Gains against Esophageal Squamous Cell Carcinoma

    Mol. Ther.

    (2020)
  • S. Ma et al.

    Identification and Characterization of Tumorigenic Liver Cancer Stem/Progenitor Cells

    Gastroenterology

    (2007)
  • W.A. Maltese et al.

    Methuosis: Nonapoptotic Cell Death Associated with Vacuolization of Macropinosome and Endosome Compartments

    Am. J. Pathol.

    (2014)
  • S. Mignani et al.

    Dendrimer– and polymeric nanoparticle–aptamer bioconjugates as nonviral delivery systems: a new approach in medicine

    Drug Discov. Today

    (2020)
  • L. Alizadeh et al.

    AS1411 aptamer-functionalized chitosan-silica nanoparticles for targeted delivery of epigallocatechin gallate to the SKOV-3 ovarian cancer cell lines

    J. Nanoparticle Res.

    (2020)
  • M.H. Amer

    Gene therapy for cancer: present status and future perspective

    Mol. Cell. Ther.

    (2014)
  • R.S. Apte

    Pegaptanib sodium for the treatment of age-related macular degeneration

    Expert Opin. Pharmacother

    (2008)
  • F. Atabi et al.

    Doxorubicin loaded DNA aptamer linked myristilated chitosan nanogel for targeted drug delivery to prostate cancer

    Iran. J. Pharm. Res.

    (2017)
  • M.S. Avila et al.

    Prevention and Treatment of Chemotherapy-Induced Cardiotoxicity

    Methodist Debakey Cardiovasc. J.

    (2019)
  • Bagalkot, Vaishali, Farokhzad, Omid C, Langer, Robert, Jon, Sangyong, Bagalkot, ] V, Jon, S, Bagalkot, V, Farokhzad, O...
  • Cited by (38)

    View all citing articles on Scopus
    View full text