Recent development of aptamer conjugated chitosan nanoparticles as cancer therapeutics
Graphical abstract
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.
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