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How Ready are Cellulose Nanocrystals in Delivery of Anticanceragents?

Ishaq Lugoloobi , Researcher, Donghua University

Public health is globally threatened by cancer and its associated effects, and these currently owe almost 13% deaths. Urgent demand of advanced, low cost and drug delivery systems to counteract cancer invasion, metastasis and most notably the mechanisms of carcinogenesis is inevitable. Natural nanomaterials like cellulose nanocrystals (CNCs) have guaranteed physical and brilliant biological properties for exploitation as future scientific technologies for reinforcement of the already established protocols for cancer therapy, especially as monitoring tools for cancer initiation and progression.

Despite the contemporary medical and life care evolution, cancer pathologies still claim high ranks in the outline of the 21st century’s globally scary diseases to populations inclusive of patients, health professionals, research specialists and authorities. As an initiation by altered and mutated normal cells that lead to uncontrolled cell proliferation and metastasis to various body parts, cancer is composed of over 200 various diseases[1]. Portentously, 12 and 11.4million cancer patients and deaths, respectively, are prophesied by 2030 [1-4]. Not with standing, scientific and technological progresses via surgery, chemo- and radiation therapeutic modalities [2, 5] possess promise of early diagnosis and consequential treatment of the various chronic cancers as “manageable” infections for a pleasing life. Theranostic is among the recent research breakthrough singularizing diagnosis and therapy for efficient therapeutic outcomes, thus hindering cancer growths at diagnosis/screening phases for consequent professional treatments[1, 6]. Theranostic systems are developed through the novel molecular imaging and delivery techniques of drugs, genes, chlorotoxin for treatment of malignant tumors, with a hand currently from nanotechnology. Screening, formulation, and administration of insoluble therapeutic moieties are simply accomplished with employment of nanotechnology[5].

The surveyed nanomaterials with appealing properties for cancer therapy include metal atoms/ions, micelles, liposomes, dendrimers, natural and synthetic polymers from various sources, using different preparation techniques [1, 7-9]. Precise control of sizes, shapes, components and surface functionalization of various nanoparticles with diverse anticancer therapeutic mechanisms have been technologically advanced for diagnosis, imaging and treatment [5]. Limitations on delivery of anticancer chemotherapeutic agents such as the very low hydrophilicity, healthy cell toxicity, low bioavailability, and also induced local and systemic inflammations with surgery, have been neutralized via nanotechnology of the exclusively futuristic biodegradable nanomaterials like CNCs.

CNCs are among the most attractive biomedical natural resources to academia and industry owed to their sustainability, biocompatibility, availability, low cost, global variety and abundancy, renewability, easy preparation, low cytotoxicity and amazing tensile properties [1, 10-12]. Industrial, agricultural, forestry and marine cellulosic products and bio-residues act as the main CNCs sources, obtainable via chemical, enzymatic, mechanical and multi-process extraction techniques after pretreatment processes like depolymerization and delignification.

Current trends

Having been invented in 1950s by Rånbyet al [13], extensive studies on CNCs were adopted after more or less a decade [14].  CNCs exist as either spherical or mostly stiff needle-like crystallites with high crystallinity and aspect ratio, optical properties, and majorly prepared chemically from strong acids by interruption of the hydrogen bond network and dissolution of amorphous domains in cellulose microfibers. With the initial CNCs functional groups including the hydroxyl, sulfate, carboxyl, acetyl moieties obtained with particular treatment techniques especially oxidation of various sources using sulfuric, hydrochloric, hydrobromic, and citric acids, and acetic acid/acetic anhydride solution, precise active chemical and/or biological groups such as polymers, photosensitizers, fluorescents, drugs, receptor peptides, ligands, chlorotoxin and genescan be linked directly or indirectly via covalent and/or noncovalent processes for anticancer functionality. Annulled self-agglomerations of CNCs with breakage of inter- and intra-molecular hydrogen bonds, improved cellular penetration efficiency and suppression of tumor activity at certain growth stages are realistic with biochemical functionalization of CNCs for efficient therapy of malignant cells. The established anticancer drugs that have been surveyed for delivery by CNCs include paclitaxel, docetaxel, etoposide, luteolin, luteoloside, tetracycline, doxorubicin, curcumin, methotrexate, coumarin, and chalcone drugs. Anticancer components such as gels (aerogels, hydrogels), bio-nanocomposites, polymer brushes, emulsions, layer-by-layer complexed thin films, microcapsules, nanoscale metal-organic frameworks/coordination polymers are the surveyed modes for manipulation of CNCs as anticancer dispensers[1].

The traditional chemotherapeutic cancer treatment measures have expressed toxicity side effects including hepatotoxicity, neurotoxicity and neuropathy, anorexia, cardiotoxicity, ototoxicity, cachexia, cognitive deficits, nephrotoxicity, fatigue and motivational deficit [1, 15]. Medicinal chemists are however, exploring cargo agents with low off target delivery of highly modified established anticancer drugs for lessened side effects(toxicity) to healthy cells. Characteristically, cargo agents with potential clinical translation should be;stable, biocompatible, nanosized for a higher internalization rate, enhanced with cell adsorption, reversible on affixation to hydrophilic and hydrophobic drugs, appropriately surface charged, delayed during blood circulation, macrophage resistant, non-toxic, non-invasive to healthy cells, vessel extravasated, sensitive to extrinsic (light, radiofrequency, magnetic field) or intrinsic (temperature, pH, redox reactions) stimuli or both, and intracellularly degradable for suppressed side effects [16]. pH sensitivity is a prominently required stimuli due to the acidic environments of cancer cells that are caused by accumulation of end products of metabolism and poor circulation of blood in tumor vessels, for a precise, timely, controlled, prolonged and enhanced release of anticancer drugs[1].

Intensive research on CNCs as future simple or non-conjugated/conjugated anticancer nanocargo agents has therefore been prioritized owed to their intracellular degradability, nano size, hydroxylated and more fluid circulative spindle shapes, with associated benefits. Cellular pathways via the actin-dependent non-specific and/or facilitated endocytic mechanisms, have been fostered for internalization of anticancer CNCs cargo in precise tumor cells, as confirmed by live imaging using fluorochromes[1, 17]. Exploitation of CNCs for cancer therapeutic applications including photoacoustic/photothermal/fluorescent bioimaging, cargo delivery, synergistic and/orcombined therapy, photodynamic therapy, have been reported viainvitro, in vivo and ex vivo experiments using various cellular and animal models to showpiece cytotoxicity to breast, brain, kidney, lung, ovarian, bone, endometrial, prostatic, colorectal tumors. Timely and controlled release, higher loading and release due to easily reversible bonds, enhanced specificity to tumor cells over the normal, rapid excretion, refined dispersion and stability, early-stage diagnoses, significant tumor lethality, prompter and enhanced response to stimuli, enhanced tolerance, higher solubility and bioavailability of drugs have been realized with employment of modified/functionalized CNCs, hence increasing survival chances against various tumors[1].

Considerably, a functionalized cellulose hydrogel expressed both photodynamic and photothermal antitumor therapy, with computerized tomography imaging monitoring of malignant cell treatment and nanocarrier degradation [18]. Immense drug load and biodegradability, as well as decimating tumor resurgence under radiation, were the multi potential characteristics of the hydrogel.

Biocompatibility

CNCs foreignness is imperative to realize their efficient functioning as delivery systems within body cells. The minimal/tolerable chemical and/or biological inertness of CNCs when in contact with healthy cells while performing their required function, normally determines their biocompatibility owed to an expectedly elicited host response. Biomaterial properties such as the molecular, physical and topological features, and host factors like age, sex, physical mobility, general health, lifestyle and status of pharmacology, usually determine biocompatibility responses. Tolerable or no cytotoxic, immunogenic, inflammatory, thrombogenic, genotoxic, carcinogenic, and hyper sensitive responses describe highly biocompatible materials.

CNCs being ultrafine particulate matter, they adsorb/bind onto protein surfaces to form stable nanoparticle-protein complexes at extents that describe their biocompatibility and biodistribution levels. Thus, CNCs were identified to express orogastrointestinal nontoxic, weak immunological, negligible hemolysis, none skin/dermal sensitization/irritation/corrosive properties depending on their concentration, especially during in vitrocell and animal model studies, and thus importance for drug delivery[1].

For instance, Shazaliet al.[19]prepared spherically shaped FITC conjugated CNCs with low cytotoxicity and high target potential to normal cells, characteristic to application as anticancer agent nanocarriers. Non-loaded CNCs capable of application via intravenous injection portrayed negligible hemolysis to erythrocytes and fascinatingly, cyto compatibility to cancer cells at moreover various concentrations[8]. Meanwhile, a great pH-responsive PTX drug-loaded nanohydrogel capable of synergistic antitumor therapy via chemotherapy and ROS-mediated oxidative damage expressed a farfetched biocompatibility to healthy cells[20].

Nevertheless, CNCs present dose dependent toxicities at specifically higher concentrations owed to certain highly varying conditions including their source, preparation procedures, treatment/modification, aggregation levels, charge density, present toxins and response from various cell models.

CNCs occupational risk exposures including inhalation, skin and eye contact, as well as their small size dependent toxicities like the cardio vascular and pulmonary irritations, should be currently the prime focus of research for CNCs toxicity.

Conclusion and perspectives

CNCs are industrially and scientifically wide spread owed to their alluring physico-chemical properties, including the various chemical modification potentials. However, their application in cancer therapy is still precocial. Despite the existing tailbacks for translation as anticancer delivery agents, commercialized CNCs production is at its prime. However, advanced biocompatibility and degradability studies, attachment of multi stimuli-responsive nanoparticles onto CNCs surfaces, and combination therapy, will enable monitoring and suppression of tumor progression with effective cancer treatment, prevent drug resistance and tumor resurgence, and thus realization of efficient and timely pharmacokinetic responses. Anticancer CNCs derivatives are thus ready for transfiguration into ointment, injectable formulations, and tablets once approved by Food and Drug Administration (FDA), given the craving necessity for their clinical translation.

References:

1.    Lugoloobi, I., et al., Cellulose nanocrystals in cancer diagnostics and treatment. J Control Release, 2021. 336: p. 207–232.
2.    Narmani, A. and S.M. Jafari, Chitosan-based nanodelivery systems for cancer therapy: Recent advances. Carbohydr Polym, 2021. 272: p. 118464.
3.    Wang, S., et al., Self-assembly of photosensitive and chemotherapeutic drugs for combined photodynamic-chemo cancer therapy with real-time tracing property. Colloids Surf. A Physicochem. Eng. Asp., 2019. 574: p. 44-51.
4.    Li, Y., et al., A pH-sensitive drug delivery system based on folic acid-targeted HBP-modified mesoporous silica nanoparticles for cancer therapy.Colloids Surf. A Physicochem. Eng. Asp., 2020. 590: p. 124470.
5.    Dhas, N., et al., Stimuli responsive and receptor targeted iron oxide based nanoplatforms for multimodal therapy and imaging of cancer: Conjugation chemistry and alternative therapeutic strategies. J Control Release, 2021. 333: p. 188-245.
6.    Horgan, C.C., et al., Integrated photodynamic Raman theranostic system for cancer diagnosis, treatment, and post-treatment molecular monitoring. Theranostics, 2021. 11(4): p. 2006-2019.
7.    Choi, J., et al., Gold nanorod-photosensitizer conjugates with glutathione-sensitive linkages for synergistic cancer photodynamic/photothermal therapy. Biotechnol. Bioeng., 2018. 115(5): p. 1340-1354.
8.    Moghaddam, S.V., et al., Lysine-embedded cellulose-based nanosystem for efficient dual-delivery of chemotherapeutics in combination cancer therapy. Carbohydr Polym, 2020. 250: p. 116861.
9.    Zhang, L., et al., Shape Effect of Nanoparticles on Tumor Penetration in Monolayers Versus Spheroids. Mol. Pharm. , 2019. 16(7): p. 2902-2911.
10.    Moon, R.J., et al., Cellulose nanomaterials review: structure, properties and nanocomposites. Chem Soc Rev, 2011. 40(7): p. 3941-3994.
11.    Seta, F.T., et al., Preparation and characterization of high yield cellulose nanocrystals (CNC) derived from ball mill pretreatment and maleic acid hydrolysis. Carbohydr Polym, 2020. 234: p. 115942.
12.    Ventura-Cruz, S. and A. Tecante, Nanocellulose and microcrystalline cellulose from agricultural waste: Review on isolation and application as reinforcement in polymeric matrices. Food Hydrocoll., 2021. 118: p. 106771.
13.    Rånby, B.G., & Ribi, E, Recent advances in nanocellulose for biomed appln.pdf- Über den Feinbau der Zellulose. Experientia, 1950. 6(1): p. 12-14.
14.    Marchessault, R.H., F.F. Morehead, and N.M. Walter, Liquid crystal systems from fibrillar polysaccharides. Nature, 1959. 184(4686): p. 632-633.
15.    Nurgali, K., R.T. Jagoe, and R. Abalo, Editorial: Adverse Effects of Cancer Chemotherapy: Anything New to Improve Tolerance and Reduce Sequelae? Front. Pharmacol. , 2018. 9(245).
16.    Sanjay, S.T., et al., Recent advances of controlled drug delivery using microfluidic platforms. Adv. Drug Deliv. Rev., 2018. 128: p. 3-28.
17.    Mohammad, I.S., et al., Drug nanocrystals: Fabrication methods and promising therapeutic applications. Int J Pharm, 2019. 562: p. 187-202.
18.    Zhang, Y., et al.,Oxidation triggered formation of polydopamine-modified carboxymethyl
cellulose hydrogel for anti-recurrence of tumor. ColloidsSurf. B: Biointerfaces. https://doi.org/10.1016/j.colsurfb.2021.112025.
19.    Shazali, N.A.H., et al., Characterization and cellular internalization of spherical cellulose nanocrystals (CNC) into normal and cancerous fibroblasts. Materials (Basel), 2019. 12(19).
20.    You, C., et al., A biocompatible and pH-responsive nanohydrogel based on cellulose nanocrystal for enhanced toxic reactive oxygen species generation. Carbohydr Polym, 2021. 258: p. 117685.

Ishaq Lugoloobi

Ishaq Lugoloobi, Researcher at Donghua University. His research interest involves nano engineering of chemical and biological materials in pure or composite form, produced especially from biobased materials for biological/chemical/pharmaceutical application. He has published research/review papers and book chapters. He has participated in international conferences including “World Pharma 2021” as an oral speaker. He is a recipient of national and international scholarships and awards.

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