Abstract
Recent advances have been made in cancer chemotherapy through the development of conjugates for anticancer drugs. Many drugs have problems of poor stability, water insolubility, low selectivity, high toxicity, and side effects. Most of the chitosan nanoparticles showed to be good drug carriers because of their biocompatibility, biodegradability, and it can be readily modified. The anticancer drug with chitosan nanoparticles displays efficient anticancer effects with a decrease in the adverse effects of the original drug due to the predominant distribution into the tumor site and a gradual release of free drug from the conjugate which enhances drug solubility, stability, and efficiency. In this review, we discuss wider applications of numerous modified chitosan nanoparticles against different tumors and also focusing on the administration of anticancer drugs through various routes. We propose the interaction between nanosized drug carrier and tumor tissue to understand the synergistic interplay. Finally, we elaborate merits of drug delivery system at the tumor site, with emphasizing future challenges in cancer chemotherapy.
Similar content being viewed by others
References
Allen TM (2002) Ligand-targeted therapeutics in anticancer therapy. Nat Rev Cancer 2:705–763
Allen TM, Martin FJ (2004) Advantages of liposomal delivery systems for anthracyclines. Semin Oncol 31:5–15
Aoshima M, Tsukagoshi S, Sakurai Y, Oh-ishi J, Ishida T (1977) N4-Behenoyl-1-beta-D-arabinofuranosylcytosine as a potential new antitumor agent. Cancer Res 37:2481–2486
Arthursson P, Edman P, Laakso T, Sjoholm I (1984) Characterization of polyacryl starch microparticles suitable as carrier for proteins and drugs. J Pharm Sci 73:1507–1513
Ashley CE, Carnes EC, Phillips GK, Padilla D, Durfee PN, Brown PA, Wharton DS, Peabody BCJ (2011) The targeted delivery of multicomponent cargos to cancer cells by nanoporous particle-supported lipid bilayers. Nat Mater 10:389–397
Balthasar S, Michaelis K, Dinauer N, von Briesen H, Kreuter J, Langer K (2005) Preparation and characterisation of antibody modified gelatin nanoparticles as drug carrier systems for uptake in lymphocytes. Biomaterials 26:2723–2732
Bhaskar N, Suresh PV, Sakhare PZ, Sachindra NM (2007) Shrimp biowaste fermentation with Pediococcus acidolactici CFR2182: Optimization of fermentation conditions by response surface methodology and effect of optimized conditions on deproteination/demineralization and carotenoid recovery. Enzyme Microb Tech 40:1427-1434
Birrenbach G, Speiser PP (1976) Polymerized micelles and their use as adjuvants in immunology. J Pharm Sci 65:1763–1766
Brack HP, Tirmizi SA, Risen WM (1997) A spectroscopic and viscometric study of the metal ion-induced gelation of the biopolymer chitosan. Polymer 38:2351–2362
Brigger I, Dubernet C, Couvreur P (2002) Nanoparticles in cancer therapy and diagnosis. Adv Drug Deliv Rev 54:631–651
Byrne JD, Betancourt T, Brannon-Peppas L (2008) Active targeting schemes for nanoparticle systems in cancer therapeutics. Adv Drug Deliv Rev 60:1615–1626
Calvo P, RemunanLopez C, VilaJato JL, Alonso MJ (1997) Chitosan and chitosan ethylene oxide propylene oxide block copolymer nanoparticles as novel carriers for proteins and vaccines. Pharm Res 14:1431–1436
Cassier PA, Walter T, Eymard B, Ardisson P, Perol M, Paillet C, Chayvialle JA, Scoazec JY, Hervieu V, Bohas CL (2009) Gemcitabine and oxaliplatin combination chemotherapy for metastatic well-differentiated neuroendocrine carcinomas: a single-center experience. Cancer 115:3392–3399
Chen WR, Korbelik M, Battels KE, Liu H, Sun J, Nordquist RE (2005) Enhancement of laser cancer treatment by a chitosan-derived immunoadjuvant. Photochem Photobiol 81:190–195
Chiu YL, Chen SC, Su CJ, Hsiao CW, Chen YM, Chen HL, Sung HWL (2009) pH-triggered injectable hydrogels prepared from aqueous N-palmitoyl chitosan: in vitro characteristics and in vivo biocompatibility. Biomaterials 30:4877–4888
Chung YC, Yeh JY, Tsai CF (2011) Antibacterial characteristics and activity of water-soluble chitosan derivatives prepared by the Maillard reaction. Molecules 16:8504–8514
Coester C, Langer K, von Briesen H, Kreuter J (2000) Gelatin nanoparticles by two step desolvation—a new preparation method, surface modifications and cell uptake. J Microencapsul 17:187–193
Couvreur P, Grislain L, Lenaerts V, Brasseur P, Guiot P, Biernacki A (1986) Biodegradable polymeric nanoparticles as drug carrier for antitumor agents. In: Guiot P, Couvreur P (eds) Polymeric nanoparticles and microspheres. CRC Press, Inc, Florida, pp 27–93
Dambies L, Vincent T, Domard A, Guibal E (2001) Preparation of chitosan gel beads by ionotropic molybdate gelation. Biomacromolecules 2:1198–1205
Damge C, Michel C, Aprahamian M, Couvreur P (1988) New approach for oral administration of insulin with polyalkylcyanoacrylate nanocapsules as drug carrier. Diabetes 37:246–251
Desai N, Trieu V, Yao Z, Louie L, Ci S, Yang A, Tao C, De T, Beals B, Dykes D, Noker P, Yao R, Labao E, Hawkins M, Soon-Shiong P (2006) Increased antitumor activity, intratumor paclitaxel concentrations, and endothelial cell transport of cremophor-free, albumin-bound paclitaxel, ABI-007, compared with cremophor-based paclitaxel. Clin Cancer Res 12:1317–1324
Drew M, Pardoll (2012) The blockade of immune checkpoints in cancer immunotherapy. Nat Rev 12:252–264
Drucker BJ, David (2003) Imatinib as a paradigm of targeted therapies. J Clin Oncol 21:2395–2455
Duncan R (2003) The dawning era of polymer therapeutics. Nat Rev Drug Discov 2:347–360
Duncan R (2006) Polymer conjugates for drug targeting. From inspired to inspiration. J Drug Target 14:333–335
Ekeblad S, Sundin A, Janson ET, Welin S, Granberg D, Kindmark H, Dunder K, Kozlovacki G, Orlefors H, Siqurd M, Oberq K, Eriksson B, Skoqseid B (2007) Temozolomide as monotherapy is effective in treatment of advanced malignant neuro endocrine tumors. Clin Cancer Res 13:2986–2991
Ferrari M (2008) Nanogeometry: beyond drug delivery. Nat Nanotechnol 3:131–132
Fire A, Xu S, Montgomery MK, Kostas SA, Driver SE, Mello CC (1998) Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans. Nature 391:806–811
Gabizon A, Martin F (1997) Polyethylene glycol-coated (pegylated) liposomal doxorubicin rationale for use in solid tumours. Drugs 54:15–21
Gabizon A, Shmeeda H, Barenholz Y (2003) Pharmacokinetics of pegylated liposomal doxorubicin: review of animal and human studies. Clin Pharmacokinet 42:419–436
Gerson SL (2002) Clinical relevance of MGMT in the treatment of cancer. J Clin Oncol 20:2388–2399
Ghafoor A, Jemal A, Cokkinides V, Cardinez C, Murray T, Samuels A, Thun MJ (2002) Cancer statistics for African Americans. CA Cancer J Clin 52:326–341
Gottesman MM, Fojo T, Bates SE (2002) Multidrug resistance in cancer: role of ATP-dependent transporters. Nat Rev Cancer 2:48–58
Gref R, Minamitake Y, Peracchia MT, Trubetskoy V, Torchilin V, Langer R (1994) Biodegradable long-circulating polymeric nano-spheres. Science 263:1600–1603
Grislain L, Couvreur P, Lenaerts V, Roland M, Deprez-De Campenere D, Speiser P (1983) Pharmacokinetics and distribution of a biodegradable drug-carrier. Int J Pharm 15:335–345
Gross CP, Smith BD, Wolf E, Andersen M (2008) Racial disparities in cancer therapy: did the gap narrow between 1992 and 2002. Cancer 112:900–908
Gurny R, Peppas NA, Harrington DD, Banker GS (1981) Development of biodegradable and injectable lattices for controlled release of potent drugs. Drug Dev Ind Pharm 7:1–25
Guyton AC, Hall JE (1996) Textbook of medical physiology, 9th edn. Elsevier, Philadelphia, p 192p
Hall LD, Yalpani MD (1980) Formation of branched-chain, soluble polysaccharides from chitosan. J Chem Soc Chem Commun 38:1153–1154
Haun JB, Devaraj NK, Hilderbrand SA, Lee H, Weissleder R (2010) Bioorthogonal chemistry amplifies nanoparticle binding and enhances the sensitivity of cell detection. Nat Nanotechnol 5:660–665
Heffernan MJ, Zaharoff DA, Fallon JK, Schlom J, Greiner JW (2011) In vivo efficacy of a chitosan/IL-12 adjuvant system for protein-based vaccines. Biomaterials 32:926–932
Henkin R (2011) Intranasal delivery to brain. Nat Biotechnol 29:480
Illum L, Davis SS (1983) Effect of the nonionic surfactant poloxamer 338 on the fate and deposition of polystyrene microspheres following intravenous administration. J Pharm Sci 72:1086–1089
Jain RK, Stylianopoulos T (2010) Delivering nanomedicine to solid tumors. Nat Rev Clin Oncol 7:653–664
Jamal A, Siegel R, Ward E, Murray T, Xu J, Smigal C, Thun MJ (2006) Cancer statistics. CA Cancer J Clin 56:106–130
Janes KA, Calvo P, Alonso MJ (2001) Polysaccharide colloidal particles as delivery systems for macromolecules. Adv Drug Deliv Rev 47:83–97
Jemal A, Siegel R, Xu J, Ward E (2010) Cancer statistics. CA Cancer J Clin 60:277–300
Jeon YJ, Kim SK (2002) Antitumor activity of chitosan oligosaccharides produced in an ultra filtration membrane reactor system. J Microbiol Biotechn 12:503–507
Jo C, Lee JW, Lee KH, Byun MW (2001) Quality properties of pork sausage prepared with water soluble chitosan oligomer. Meat Sci 59:369–375
Kast CE, Bernkop-Schnurch A (2002) Polymer-cysteamine conjugates: new mucoadhesive excipients for drug delivery. Int J Pharm 234:91–99
Kato Y, Onishi H, Machida Y (2001) Biological characteristics of lactosaminated N-succinyl-chitosan as a liver-specific drug carrier in mice. J Control Release 70:295–307
Kato Y, Onishi H, Machida Y (2004) N-succinyl-chitosan as a drug carrier: water-insoluble and water-soluble conjugates. Biomaterials 25:907–915
Kato Y, Onishi H, Machida Y (2002) Depolymerization of N-succinyl-chitosan by hydrochloric acid. Carbohydr Res 337:561–562
Kattan J, Droz JP, Couvreur P, Marino JP, Boutan-Laroze A, Rougier P, Brault P, Vranckx H, Grognet JM, Morge X, Sancho-Garnier H (1992) Phase I clinical trial and pharmacokinetic evaluation of doxorubicin carried by polyisohexylcyanoacrylate nanoparticles. Invest New Drugs 10:191–199
Khanna SC, Jecklin T, Speiser P (1970) Bead polymerisation technique for sustained release dosage form. J Pharm Sci 59:614–618
Khanna SC, Speiser P (1969) Epoxy resin beads as a pharmaceutical dosage form I: methods of preparation. J Phar Sci 58:1114–1117
Kim JH, Kim YS, Park K, Lee S, Nam HY, Min KH, Jo HG, Park JH, Choi K, Jeong SY, Park RW, Kim IS, Kim K, Kwon IC (2008) Antitumor efficacy of cisplatin-loaded glycol chitosan nanoparticles in tumor-bearing mice. J Control Release 7(127):41–49
Kono A, Hara Y, Sugata S, Karube Y, Matsushima Y, Ishitsuka H (1983) Activation of 5′-deoxy-5-fluorouridine by thymidine phosphorylase in human tumors. Chem Pharm Bull 31:175–178
Kopf H, Joshi RK, Soliva M, Speiser P (1977) Studium der Mizellpolymerisation in Gegenwart niedermolekularer Arzneistoffe. Bindungsartvon inkorporierten niedermolekularen Modellarzneistoffen an Nanopartikel auf Polyacrylamid-Basis. Restmonomerenbestimmung, physikalisch-chemische. Daten Pharm Ind 39:993–997
Kreuter J (1983) Physicochemical characterization of polyacrylic nanoparticles. Int J Pharm 14:43–58
Kulke MH, Stuart K, Enzinger PC, Ryan DP, Clark JW, Muzikansky A, Vincitore M, Michelini A, Fuchs CS (2006) Phase II study of temozolomide and thalidomide in patients with metastatic neuroendocrine tumors. J Clin Oncol 24:401–406
Kumar MN, Muzzarelli RA, Muzzarelli C (2004) Chitosan chemistry and pharmaceutical perspectives. Chem Rev 104:6017–6084
Kumar V, Banker GS (1996) Target-oriented drug delivery systems. In: Banker GS, Rhodes CT. Modern pharmaceutics. New York: Marcel Dekker, Inc.,:611-680
Kwekkeboom DJ, de Herder WW, Kam BL, van Eijck CH, van Essen M, Kooij PP, Feelders RA, van Aken MO, Krenning EP (2008) Treatment with the radiolabeled somatostatin analog [177 Lu-DOTA 0, Tyr3] octreotate: toxicity, efficacy, and survival. J Clin Oncol 26:2124–2130
LaVan DA, McGuire T, Langer R (2003) Small-scale systems for in vivo drug delivery. Nat Biotechnol 21:1184–1191
Le Tien C, Lacroix M, Ispas Szabo P, Mateescu MA (2003) N-acylated chitosan: hydrophobic matrices for controlled drug release. J Control Release 93:1–13
Limin XC, Eric JF, Douglas NM, Michael PF, Benjamin FH (2002) Impact of reporting delay and reporting error on cancer incidence rates and trends. J Natl Cancer Inst 94:1537–1545
Maeda H (2001) The enhanced permeability and retention (EPR) effect in tumor vasculature: the key role of tumor-selective macromolecular drug targeting. Adv Enzyme Regul 41:189–207
Maincent P, Le Verge R, Sado PA, Couvreur P, Devissaguet JP (1986) Disposition kinetics and oral bioavailability of vincamine-loaded polyalkyl cyanoacrylate nanoparticles. J Pharm Sci 75:955–9558
Marty JJ, Oppenheim RC (1977) Colloidal systems for drug delivery. Aust J Pharm Sci 6:65–76
Miele E, Spinelli GP, Tomao F, Tomao S (2009) Albumin-bound formulation of paclitaxel (Abraxane ABI-007) in the treatment of breast cancer. Int J Nanomed 4:99–105
Mills JK, Needham D (1999) Targeted drug delivery. Expert Opin Ther Patents 9:1499–1513
Moschos SA, Bramwell VW, Somavarapu S, Alpar HO (2004) Adjuvant synergy: the effects of nasal coadministration of adjuvants. Immunol Cell Biol 82:628–637
Murata J, Ohya Y, Ouchi T (1997) Design of quaternary chitosan conjugate having antennary galactose residues as a gene delivery tool. Carbohyd Polym 32:105–109
Muzzarelli RAA, Muzzarelli C (2009) Chitin and chitosan hydrogels. In: Phillips GO, Williams PA (eds) Handbook of hydrocolloids. Woodhead, Inc., Cambridge, pp 1849–1888
Muzzarelli RAA (1997) Human enzymatic activities related to the therapeutic administration of chitin derivatives. Cell Mol Life Sci 53:131–140
Nsereko S, Amiji M (2002) Localized delivery of paclitaxel in solid tumors from biodegradable chitin microparticle formulations. Biomaterials 23:2723–2731
Park IK, Yang J, Jeong HJ, Bom HS, Harada I, Akaike T, Kim SI, Cho CS (2003) Galactosylated chitosan as a synthetic extracellular matrix for hepatocytes attachment. Biomaterials 24:2331–2337
Pastan I, Hassan R, FitzGerald DJ, Kreitman RJ (2006) Immunotoxin therapy of cancer. Nat Rev Cancer 6:559–565
Peer D, Karp JM, Hong S, Farokhzad OC, Margalit R, Langer R (2007) Nanocarriers as an emerging platform for cancer therapy. Nat Nanotechnol 2:751–760
Pericleous P, Gazouli M, Lyberopoulou A, Rizos S, Nikiteas N (2012) Efstathopoulos EP Quantum dots hold promise for early cancer imaging and detection. Int J Cancer 131:519–528
Pillai CKS, Paul W, Sharma CP (2009) Chitin and chitosan polymers: chemistry, solubility and fiber formation. Prog Polym Sci 34:641–678
Prameela K, Murali Mohan CH, Hemalatha KPJ (2010a) Extraction of pharmaceutically important chitin and carotenoids from shrimp biowaste by microbial fermentation method. J Pharm Res 3:2393–2395
Prameela K, Murali Mohan CH, Hemalatha KPJ (2010b) Bio-efficiency of Pediococcus acidilactici (ATCC 8042) for recovery of chitin and carotenoids in the fermentation of shrimp biowaste. Int J ChemTech Res 2:1924–1928
Prameela K, Murali Mohan CH, Hemalatha KPJ (2012) Efficient use of shrimp waste: present and future trends. Appl Micro Bio 93:17–29
Prameela K, Murali Mohan CH, Smitha PV, Hemalatha KPJ (2010c) Bioremediation of shrimp biowaste by using natural probiotic for chitin and carotenoid production an alternative method to hazardous chemical method. Int J Appl Biol Pharm Technol 1:903–910
Ravi Kumar MNV, Muzzarelli RAA, Muzzarelli C, Sashiwa H, Domb AJ (2004) Chitosan chemistry and pharmaceutical perspective. Chem Rev 104:6017–6084
Rinaudo M (2006) Chitin and chitosan: properties and applications. Prog Polym Sci 31:603–632
Sato M, Onishi H, Takahara J, Machida Y, Nagai T (1996) In vivo drug release and antitumor characteristics of water-soluble conjugates of mitomycin C with glycol-chitosan and N-succinylchitosan. Biol Pharm Bull 19:1170–1177
Serpe L (2006) Conventional chemotherapeutic drug nanoparticles for cancer treatment. In: Kumar CSSR (ed) Nanomaterials for cancer therapy. Wiley-VCH, Inc, Weinheim, pp 1–39
Shuming N, Yun X, Gloria JK, Jonathan WS (2007) Nanotechnology applications in cancer. Annu Rev Biomed Eng 9:257–288
Siegel R, Naishadham D, Jemal A (2013) Cancer statistics 2013. CA Cancer J Clin 63:11–30
Smith RA, Mettlin CJ, Davis KJ, Eyre H (2000) American Cancer Society guidelines for the early detection of cancer. CA Cancer J Clin 50:34–49
Song Y, Onishi H, Machida Y, Nagai T (1996) Drug release and antitumor characteristics of N-succinyl-chitosan-mitomycin C as an implant. J Control Release 42:93–100
Song Y, Onishi H, Nagai T (1993) Conjugate of mitomycin C with N-succinyl-chitosan-mitomycin C: in vitro drug release properties, toxicity and antitumor activity. Int J Pharm 98:121–130
Strebhardt K, Ullrich A (2008) Paul Ehrlich’s magic bullet concept: 100 years of progress. Nat Rev Cancer 8:473–480
Struszczyk MH (2006) Global requirements for medical applications of chitin and its derivatives. In: Lodz (ed) Polish Chitin Society. Monograph XI, Inc, Poland, pp 95–102
Sun C, Lee JS, Zhang M (2008) Magnetic nanoparticles in MR imaging and drug delivery. Adv Drug Deliv Rev 60:1252–1265
Suzuki K, Mikami T, Okawa Y, Tokoro A, Suzuki M (1987) Antitumor effect of hexa-N-acetylchitohexaose and chitohexaose. Carbohyd Res 151:403–408
Synowiecki J, Al-Khateeb NA (2003) Production, properties, and some new applications of chitin and its derivatives. Crit Rev Food Sci Nutr 43:145–171
Torrecilla D, Lozano MV, Lallana E, Neissa JI, Novoa-Carballal R, Vidal A, Fernandez-Megia E, Torres D, Riguera R, Alonso MJ, Dominguez F (2013) Anti-tumor efficacy of chitosan-g-poly(ethylene glycol) nanocapsules containing docetaxel: anti-TMEFF-2 functionalized nanocapsules vs. non-functionalized nanocapsules. Eur J Pharm Biopharm 83:330–337
Trouet A, Masquelier M, Baurain R, Deprez-De CD (1982) A covalent linkage between daunorubicin and proteins that is stable in serum and reversible by lysosomal hydrolases, as required for a lysosomotropic drug-carrier conjugate: in vitro and in vivo studies. Proc Natl Acad Sci 79:626–629
Tsukada K, Matsumoto T, Aizawa K, Tokoro A, Naruse R, Suzuki S, Suzuki M (1990) Antimetastatic and growth-inhibitory effects of N-acetylchitohexaose in mice bearing Lewis lung carcinoma. Jpn J Cancer Res 81:259–265
Ueno H, Murakami M, Okumura M, Kadosawa T, Uede T, Fujinaga T (2001) Chitosan accelerates the production of osteopontin from polymorphonuclear leukocytes. Biomaterials 22:1667–1673
van der Lubben IM, Verhoef JC, Borchard G, Junginger HE (2001) Chitosan for mucosal vaccination. Adv Drug Deliv Rev 52:139–144
van Kouwenhove M, Kedde M, Agami R (2011) MicroRNA regulation by RNA-binding proteins and its implications for cancer. Nat Rev Cancer 11:644–656
Vanneman M, Dranoff G (2012) Combining immunotherapy and targeted therapies in cancer treatments. Nat Rev 12:237–251
Vivier E, Ugolini S, Blaise D, Chabannon C, Brossay L (2012) Targeting natural killer cells and natural T cells in cancer. Nat Rev Immunol 12:239–252
von Maltzahn G, Park JH, Lin KY, Singh N, Schwöppe C, Mesters R, Berdel WE, Ruoslahti E, Sailor MJ, Bhatia SN (2011) Nanoparticles that communicate in vivo to amplify tumour targeting. Nat Mater 10:545–552
Wang JJ, Zeng ZW, Xiao RZ, Xie T, Zhou GL, Zhan XR, Wang SL (2011) Recent advances of chitosan nano particles as drug carriers. Int J Nanomedicine 6:765–774
Yang R, Yang SG, Shim WS, Cui F, Cheng G, Kim IW, Kim DD, Chung SJ, Shim CK (2009) Lung-specific delivery of paclitaxel by chitosan-modified PLGA nanoparticles via transient formation of microaggregates. J Pharm Sci 98:970–984
Yu MK, Park J, Jon S (2012) Targeting strategies for multifunctional nanoparticles in cancer imaging and therapy. Theranostics 2:3–44
Zaharoff DA, Rogers CJ, Hance KW, Schlom J, Greiner JW (2007) Chitosan solution enhances both humoral and cell-mediated immune responses to subcutaneous vaccination. Vaccine 25:2085–2094
Zhang L, Gu FX, Chan JM, Wang AZ, Langer RS, Farokhzad OC (2008) Nanoparticles in medicine: therapeutic applications and developments. Clin Pharmacol Ther 83:761–769
Zou A, Huo M, Zhang Y, Zhou J, Yin X, Yao C, Zhu Q, Zhang M, Ren J, Zhang Q (2012) Octreotide-modified N-octyl-O, N-carboxymethyl chitosan micelles as potential carriers for targeted antitumor drug delivery. J Pharm Sci 101:627–640
Acknowledgments
KP is grateful to Dr. Rajkumar Savai for helpful discussion.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Kandra, P., Kalangi, H.P. Current understanding of synergistic interplay of chitosan nanoparticles and anticancer drugs: merits and challenges. Appl Microbiol Biotechnol 99, 2055–2064 (2015). https://doi.org/10.1007/s00253-015-6384-9
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00253-015-6384-9