Pharma Focus Asia

Smart Polymeric Nanocomposites for Cancer Therapeutics

Saurabh Shivalkar, Department of Applied Sciences, Indian Institute of Information Technology

Sneha Ranjan, Department of Biotechnology, Babasaheb Bhimrao Ambedkar University

Smart polymeric nanocomposites respond specifically to stimuli such as pH, temperature, biochemical or magnetic field. This provides a scope for smart modulation of the encapsulated drug for its sustained and controlled release, specifically at hard-to-reach organs or tissues such as cancer-affected areas. Therefore, minimising the impact of side-effects caused because of drugs on normal cells or tissues.

Globally, cancer is the second most prevalent healthcare issue, following cardiovascular. Conventional methods such as chemotherapy and radiotherapy have several detrimental side effects without guaranteed permanent recovery. In the last few decades, efforts have been made by introducing nanotechnology to cancer therapeutics. Owing to the size range of the nanomaterials i.e., 1 nm to 500 nm (1 nanometre is one-billionth of a meter) with remarkable physiological properties, provided scope for diagnosis at early stage and therapeutics at a cellular level. Recently, nanoengineering of the structural aspects of the nanomaterials has significantly improved their properties and has functional advantages over their bulk counterpart. Polymeric nanocomposites are one such example, where a polymer matrix constitutes homogenously dispersed nanofillers or nanoparticles to obtain better physiochemical properties. Physiological properties play a great role in the interaction and functioning of polymeric nanocomposites at the biological surfaces. The ratios of polymer matrix and nanomaterials could easily be modulated to control the surface charge and surface chemistry of the polymeric nanocomposites. Consequently, providing smart properties such as self-healing, intelligent sensing, shape memory and self-cleaning to different polymeric nanocomposites. Additionally, the use of natural or derived polymers for the synthesis of polymeric nanocomposites makes them low toxic and biocompatible. Therefore, they provide an opportunity for innovative healthcare and biomedicine application in the areas of stimuli-response such as cancer therapeutics.

Conventional anticancer drugs have several limitations like short half-life, low absorption and specificity, low therapeutic index, a large volume of distribution, insufficient bioavailability, instability in blood circulation and cytotoxicity. Smart polymeric nanocomposites are believed to possess one or more physical or chemical properties that could easily be controlled using internal stimuli (such as pH, solvent, chemical, biochemical etc.) or external stimuli (such as temperature, magnetic field, light, ultrasound etc.). Therefore, scientific research on the advancement and development of smart polymeric nanocomposite is rapidly growing for cancer therapeutics due to (1) efficient drug encapsulation; (2) easy interaction between drug and antibody, peptides, aptamer etc.; (3) controlled (specific amount) and sustained (over a specific period) drug release at the targeted sites; (4) very low inflammatory response and immunogenicity; (5) biodegradable and economic. The nanocarriers designed using these smart polymeric nanocomposites are targeted to the tumour site to overcome the above-mentioned limitations of anticancer drugs. The major advantage of these nanocarriers is sustained release in blood circulation to reduce the frequent uptake of the drug. Therefore, making it promising feature to maintain the release profile of anticancer therapeutic drugs through some intracellular stimuli such as blood sugar, pH, oxygen levels, ionic strength, internal temperature, and enzymes.

The polymeric nanocomposites are generally prepared using solution mixing, melt intercalation, in-situ polymerisation, template synthesis etc. However, the preparation of efficient polymeric nanocomposite required the selection of an appropriate synthesis method depending on the physical and chemical properties of the polymer. Natural and derived polymers such as chitosan, cellulose, alginate, collagen etc., are frequently used for the synthesis of these composites. Natural polymers offer some unique mechanical properties. However, it often comes with the limitation of time-consuming extraction and purification processes. On the other hand, nanomaterials are can be synthesized in different shapes and sizes that could provide very large interfacial areas post-dispersion into a polymer matrix. However, the limitation of nanomaterials aggregation prevents their efficient dispersion into the polymer matrices. To obtain high-performance polymeric nanocomposites good dispersion of nanomaterials is a must. Therefore, a specific combination of polymer and nanomaterials is used during synthesis to obtain good dispersion. Moreover, a high aspect ratio of nanomaterials is most important for loading drugs into the polymeric nanocomposites.  For biological applications, primarily metal or metal oxide nanomaterials (such as gold, silver, copper, iron oxide, zinc oxide nanoparticles etc.) and carbon-based nanomaterials (carbon nanotubes, graphene, graphene-oxide, carbon dots) are combined with anticancer drug coupled/impregnated suitable polymeric matrix to form polymeric nanocomposite drug carriers. Drug delivery system can be targeted via two processes:
Active targeting: It is based on receptor-ligand interaction, where a specific ligand-tagged polymeric nanocomposite drug carrier is targeted towards tumorous cells having respective receptors. Therefore, destroying only tumorous cells without affecting healthy cells. Hence, increases the selectivity of the cell which ultimately reduces the chance of cytotoxicity and side effects with an unwanted distribution of drugs within the entire body.

Passive targeting: It is based on the enhanced permeability and retention (EPR) effect. Drug-loaded polymeric nanocomposites of certain sizes (200 nm) can permeate only through leaky vasculature such as tumour tissues. Therefore, more effective on tumour tissues without accumulating much towards normal tissues. These drugs are targeted to the affected site by the body’s natural immune system which enhances its circulation for a longer time and protects clearance either by the reticuloendothelial system or opsonisation. This functionality is achieved by using hydrophilic polymers such as polyethylene glycol during the synthesis of polymeric nanocomposites.

Conventional drug delivery methods required frequent intake of medicines that are painstaking for the person and sometimes it is challenging under certain medical conditions or in the case of infants. Therefore, smart polymeric nanocomposites-based drug carrier has a 'programmable period' that can provide a sustained release over a longer period with a specific required amount of therapeutic doses only and could significantly reduce the drug uptake. Therefore, a proper release profile can be managed easily over a longer period. Some of the polymeric nanocomposites developed for cancer therapeutics are briefly described:

PLGA-Silver nanocomposite: Silver nanoparticles shows both antimicrobial as well as an anticancer activity depending on the factors like size, shape, surface charge, functional group, and stages of cell division. Poly (lactic-co-glycolic acid) (PLGA) was combined with silver nanoparticles to encapsulate an anticancer agent like recombinant interferon-gamma (a recombinant protein) to facilitate both tumoricidal and antiviral activity. Anticancer agent encapsulated PLGA-Silver nanocomposite was used for the imaging and treatment of breast cancer (MCF-7 cells) as well as cervical cancer (HeLa cells). The anticancer activity was due to recombinant protein causing apoptosis-mediated programmed cell death via cell cycle arrest, DNA damage, cell membrane destabilisation and oxidative stress.1

PLA-Iron oxide-MWCNT nanocomposite: Multi-walled carbon nanotubes (MWCNTs) and iron oxide nanoparticles were dispersed into Daunorubicin-loaded polylactic acid (PLA) to form nanofibrous scaffolds. This nanofibrous scaffold has an inhibition effect on the leukaemia K562 cell lines. The magnetic properties offered by the iron oxide nanoparticles in the nanofibrous scaffold could control the Daunorubicin delivery to the leukaemia cancer cells. 2

Cellulose-Iron oxide nanocomposite:  Cellulose is a biopolymer composed of repeating units of D-glucose linked via beta-1,4 glycosidic linkage. Cellulose is produced by plants, algae, and some microorganisms. Curcumin (drug) loaded iron oxide nanoparticle was dispersed in the cellulose to form a nanocarrier for the in-vitro treatment of colon cancer. The smart feature of these nanocarriers is they can be magnetically triggered and controlled from outside during the therapeutic process. Additionally, cellulose nanocarriers of size range 10-100 nm exhibit hydrophilic interaction and hydrogen-bond formation, thus enhancing the physiological efficiency of the drug delivery system. 3

Chitosan-Gold-Nucleic acid nanocomposite: Chitosan is naturally obtained by removing the acetyl group of chitins present in shrimps, crabs, shells of lobsters, prawns, and crustaceans. Chitosan is a cationic polymer suitable for drug targeting through various routes of administration (e.g.: intravenous, subcutaneous, inhaled, and intramuscular route) has several properties like low immunogenicity, antitumor, antimicrobial activity, wound healing, good adhesion, and coagulation. Chitosan can also form polyplexes with nucleic acid through electrostatic interaction. Based on this interaction, a cytosine deaminase uracil phosphoribosyl transferase (CD-UPRT) suicide gene loaded chitosan-gold nanocluster nanocomposite was developed that produces CD-UPRT enzyme to inhibit DNA replication and transcription within the tumour cells. Thus, neutralising the tumour cells. Furthermore, the gold nanoclusters being highly fluorescent assist in tracking the movement of the nanocomposite through microscopic images. 4

Chitosan-Graphene nanocomposite: An anticancer drug (e.g.: doxorubicin hydrochloride) delivery is mediated by developing self-assembly of chitosan/sodium-alginate with graphene oxide nanosheets loaded magnetic iron oxide nanoparticles to form a polymeric nanocomposite. The average size of this nanocomposite was approximately 50 nm to which doxorubicin hydrochloride is loaded through electrostatic interaction to expedite superparamagnetic property, thus targeting magnetic cellular uptake.5

Polymeric Micelles-Silver nanocomposite: Polymeric micelles derived from the self-assembly of poly (ethylene oxide)-b-poly (n-butyl acrylate)-b-poly (acrylic acid) triblock terpolymer was used for the development of nanocomposite. Herein, a poly (acrylic acid) block of triblock terpolymer has been used for the dispersion of silver nanoparticles while a poly (n-butyl acrylate) hydrophobic core was used for the encapsulation of the curcumin. Some reports are also available stating silver nanoparticles are not only a good antimicrobial agent but also an anticancer agent. Therefore, triblock terpolymer-based nanocomposites have two anticancer agents i.e., curcumin and silver nanoparticles. Enhanced cytotoxicity was observed through an in-vivo study on acute myeloid leukaemia (HL-60) and human urinary bladder carcinoma (EJ) cells when combined doses of both anticancer agents were released from the nanocomposites.2

Polylysine-PLGA-nanocomposite: Polymeric nanocomposite formed using different types of lysine homopolymers (polylysine) coating over the Tamoxifen-loaded poly (lactic-co-glycolic acid) (PLGA) nanoparticles. The hydrophobic matrix of the PLGA could provide more than 80% loading efficiency of the Tamoxifen drug. The nanocomposite was found effective against breast adenocarcinoma cells. 2

Hyaluronic acid-testosterone nanocomposite: Self-assembled hyaluronic acid/testosterone nanocomposite was used for the encapsulation of the drugs, Camptothecin and Doxorubicin. In an in-vitro study, it was found that such nanocomposites have promising results in chemotherapy.2
Polymeric nanocomposites have tremendous possibilities in cancer therapeutics and could become an integral part of the cutting-edge modern technology associated with biomedical engineering.

References

1.    Sahoo, et al., ACS Appl. Mater. Interfaces, 2014, 6, 712–724.
2.    Feldman, Applied Sciences, 2019, 9, 3899.
3.    Low, et al., International Journal of Biological Macromolecules, 2019, 127, 76–84.
4.    Sahoo, et al., ACS Biomater. Sci. Eng., 2016, 2, 1395–1402.
5.    Xie, et al., Colloids and Surfaces B: Biointerfaces, 2019, 176, 462–470.

Saurabh Shivalkar

Saurabh Shivalkar is a research fellow at Department of Applied Sciences, IIIT Allahabad, India. He did his M. Tech (Biomedical Engineering) from IIIT Allahabad. He has recently filed patent and published multiple papers in the allied areas of biomedical engineering and nanobiotechnology.

Sneha Ranjan

Sneha Ranjan is currently pursuing M.Sc. (Biotechnology) at Department of Biotechnology of Babasaheb Bhimrao Ambedkar University, Lucknow. She has worked on projects such as purification and characterisation of enzyme, production of recombinant proteins for diagnostics and therapeutics. She is currently working on polymeric nanocomposites for cancer therapeutics.

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