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Oncology is that area of medicine where patients are usually treated intravenously. Researchers are trying to find alternative drug delivery methods of anticancer drugs due to the pain associated with conventional drug delivery methods. Studies estimate that a majority of patients (up to 89%) prefer oral anticancer medications to traditional IV fluid or injection therapies when available. Better patient compliance, tolerability, reduced cost; greatest safety and possible increased efficacy are the main reasons for increased attention towards oral delivery of anti-cancer drugs. But oral bioavailability of this class is limited because of its idiosyncratic physicochemical properties and biological barriers such as pre-systemic metabolism and gastrointestinal instability. The various challenges to oral delivery of anticancer drugs are discussed extensively in this paper including peculiar physicochemical properties, biological barriers and adverse drug-drug interactions. Further, the emerging innovations in addressing the challenges to oral delivery of anticancer drugs are discussed. These mainly include absorption enhancers and nanocarriers based drug delivery systems.
Ruddy K, Mayer E, Partridge A. Patient adherence and persistence with oral anticancer treatment. CA Cancer J Clin. 2009;59:56–66. Available:https://doi.org/10.3322/caac.20004
Ferrari M. Cancer nanotechnology: Opportunities and challenges. Nat Rev Cancer. 2005;5:161–71.
Liu G, Franssen E, Fitch MI, Warner E. Patient preferences for oral versus intravenous palliative chemotherapy. J Clin Oncol. 1997;15:110–5.
Kuppens IELM, Bosch TM, Van Maanen MJ, Rosing H, Fitzpatrick A, Beijnen JH, et al. Oral bioavailability of docetaxel in combination with OC144-093 (ONT-093). Cancer Chemother Pharmacol. 2005;55: 72–8. Available:https://doi.org/10.1007/s00280-004-0864-4
Peltier S, Oger JM, Lagarce F, Couet W, Benoît JP. Enhanced oral paclitaxel bioavailability after administration of paclitaxel-loaded lipid nanocapsules. Pharm Res. 2006;23:1243–50.
Koolen SLW, Beijnen JH, Schellens JHM. Intravenous-to-oral switch in anticancer chemotherapy: A focus on docetaxel and paclitaxel. Clin Pharmacol Ther. 2010;87: 126–9. Available:https://doi.org/10.1038/clpt.2009.233
Tabata T, Katoh M, Tokudome S, Hosakawa M, Chiba K, Nakajima M, et al. Bioactivation of capecitabine in human liver: Involvement of the cytosolic enzyme on 5′-deoxy-5-fluorocytidine formation. Drug Metab Dispos. 2004;32:762–7.
Choi JS, Jo BW. Enhanced paclitaxel bioavailability after oral administration of pegylated paclitaxel prodrug for oral delivery in rats. Int J Pharm. 2004;280: 221–7. Available:https://doi.org/10.1016/j.ijpharm.2004.05.014
Fayad W, Rickardson L, Haglund C, Olofsson MH, D’Arcy P, Larsson R, et al. Identification of Agents that Induce Apoptosis of Multicellular Tumour Spheroids: Enrichment for Mitotic Inhibitors with Hydrophobic Properties. Chem Biol Drug Des. 2011;78:547–57.
Kalaria DR, Sharma G, Beniwal V, Ravi Kumar MNV. Design of biodegradable nanoparticles for oral delivery of doxorubicin: In vivo pharmacokinetics and toxicity studies in rats. Pharm Res. 2009; 26:492–501. Available:https://doi.org/10.1007/s11095-008-9763-4
Gambhire VM, Salunkhe SM, Gambhire MS. Atorvastatin-loaded lipid nanoparticles: antitumor activity studies on MCF-7 breast cancer cells. vol. 44. Taylor & Francis; 2018.
Babu NJ, Sanphui P, Nangia A. Crystal Engineering of Stable Temozolomide Cocrystals. 2012:1–13.
Thanki K, Gangwal RP, Sangamwar AT, Jain S. Oral delivery of anticancer drugs: Challenges and opportunities. J Control Release. 2013;170:15–40.
Bhardwaj V, Ankola DD, Gupta SC, Schneider M, Lehr CM, Kumar MNVR. PLGA nanoparticles stabilized with cationic surfactant: Safety studies and application in oral delivery of paclitaxel to treat chemical-induced breast cancer in rat. Pharm Res. 2009;26:2495–503.
Porat D, Dahan A. Active intestinal drug absorption and the solubility-permeability interplay. vol. 537. Elsevier B.V.; 2018.
Aulton ME. Chapter 25 Granulation. Pharm Sci Dos Form Des. 2001:364–78.
Singh BN, Malhotra BK. Effects of food on the clinical pharmacokinetics of anticancer agents. Clin Pharmacokinet. 2004;43: 1127–56. Available:https://doi.org/10.2165/00003088-200443150-00005
Thummel KE, Kunze KL, Shen DD. Enzyme-catalyzed processes of first-pass hepatic and intestinal drug extraction. Adv Drug Deliv Rev. 1997;27:99–127.
Bansal T, Akhtar N, Jaggi M, Khar RK, Talegaonkar S. Novel formulation approaches for optimising delivery of anticancer drugs based on P-glycoprotein modulation. Drug Discov Today. 2009; 14:1067–74. Available:https://doi.org/10.1016/j.drudis.2009.07.010
Werle M. Natural and synthetic polymers as inhibitors of drug efflux pumps. Pharm Res. 2008;25:500–11.
Chen C, Zhou J, Ji C. Quercetin: A potential drug to reverse multidrug resistance. Life Sci. 2010;87:333–8.
Shin SC, Choi JS, Li X. Enhanced bioavailability of tamoxifen after oral administration of tamoxifen with quercetin in rats. Int J Pharm. 2006;313:144–9.
Johnson BM, Charman WN, Porter CJH. An in vitro examination of the impact of polyethylene glycol 400, pluronic p85, and vitamin e d-a-tocopheryl polyethylene glycol 1000 succinate on p-glycoprotein efflux and enterocyte-based metabolism in excised rat intestine. AAPS J. 2002; 4.
Ashiru-Oredope DAI, Patel N, Forbes B, Patel R, Basit AW. The effect of polyoxyethylene polymers on the transport of ranitidine in Caco-2 cell monolayers. Int J Pharm. 2011;409:164–8.
qbal J, Hombach J, Matuszczak B, Bernkop-Schnürch A. Design and in vitro evaluation of a novel polymeric P-glycoprotein (P-gp) inhibitor. J Control Release. 2010;147:62–9.
Hugger ED, Audus KL, Borchardt RT. Effects of poly(ethylene glycol) on efflux transporter activity in Caco-2 cell monolayers. J Pharm Sci. 2002;91:1980–90.
Werle M, Hoffer M. Glutathione and thiolated chitosan inhibit multidrug resistance P-glycoprotein activity in excised small intestine. J Control Release. 2006;111:41–6. Available:https://doi.org/10.1016/j.jconrel.2005.11.011
Rege BD, Kao JPY, Polli JE. Effects of nonionic surfactants on membrane transporters in Caco-2 cell monolayers. Eur J Pharm Sci. 2002;16:237–46.
Sha X, Yan G, Wu Y, Li J, Fang X. Effect of self-microemulsifying drug delivery systems containing Labrasol on tight junctions in Caco-2 cells. Eur J Pharm Sci. 2005;24:477–86. Available:https://doi.org/10.1016/j.ejps.2005.01.001
Yamagata T, Kusuhara H, Morishita M, Takayama K, Benameur H, Sugiyama Y. Effect of excipients on breast cancer resistance protein substrate uptake activity. J Control Release. 2007;124:1–5.
Upadhyay AK, Singh S, Chhipa RR, Vijayakumar MV, Ajay AK, Bhat MK. Methyl-β-cyclodextrin enhances the susceptibility of human breast cancer cells to carboplatin and 5-fluorouracil: Involvement of Akt, NF-κB and Bcl-2. Toxicol Appl Pharmacol. 2006;216:177–85.
Agüeros M, Ruiz-Gatón L, Vauthier C, Bouchemal K, Espuelas S, Ponchel G, et al. Combined hydroxypropyl-β-cyclodextrin and poly(anhydride) nanoparticles improve the oral permeability of paclitaxel. Eur J Pharm Sci. 2009;38:405–13.
Roger E, Lagarce F, Garcion E, Benoit JP. Biopharmaceutical parameters to consider in order to alter the fate of nanocarriers after oral delivery. Nanomedicine. 2010;5: 287–306. Available:https://doi.org/10.2217/nnm.09.110
Lai SK, Wang YY, Hanes J. Mucus-penetrating nanoparticles for drug and gene delivery to mucosal tissues. Adv Drug Deliv Rev. 2009;61:158–71.
Deli MA. Potential use of tight junction modulators to reversibly open membranous barriers and improve drug delivery. Biochim Biophys Acta - Biomembr. 2009;1788:892–910.
Roger E, Lagarce F, Garcion E, Benoit JP. Lipid nanocarriers improve paclitaxel transport throughout human intestinal epithelial cells by using vesicle-mediated transcytosis. J Control Release. 2009; 140:174–81. Available:https://doi.org/10.1016/j.jconrel.2009.08.010
Jain S, Valvi PU, Swarnakar NK, Thanki K. Gelatin coated hybrid lipid nanoparticles for oral delivery of Amphotericin B. Mol Pharm. 2012;9:2542–53.
Harde H, Das M, Jain S. Solid lipid nanoparticles: An oral bioavailability enhancer vehicle. Expert Opin Drug Deliv. 2011;8:1407–24. Available:https://doi.org/10.1517/17425247.2011.604311
Jacobs C, Kayser O, Müller RH. Production and characterisation of mucoadhesive nanosuspensions for the formulation of bupravaquone. Int J Pharm. 2001;214:3–7. Available:https://doi.org/10.1016/S0378-5173(00)00622-0
Garnett MC. Targeted drug conjugates: Principles and progress. Adv Drug Deliv Rev. 2001;53:171–216.
Deng J, Huang L, Liu F. Understanding the structure and stability of paclitaxel nanocrystals. Int J Pharm. 2010;390:242–9. Available:https://doi.org/10.1016/j.ijpharm.2010.02.013
Jain AK, Swarnakar NK, Das M, Godugu C, Singh RP, Rao PR, et al. Augmented anticancer efficacy of doxorubicin-loaded polymeric nanoparticles after oral administration in a breast cancer induced animal model. Mol Pharm. 2011;8:1140–51.
Jain AK, Swarnakar NK, Godugu C, Singh RP, Jain S. The effect of the oral administration of polymeric nanoparticles on the efficacy and toxicity of tamoxifen. Biomaterials. 2011;32:503–15.
Rajpoot P, Bali V, Pathak K. Anticancer efficacy, tissue distribution and blood pharmacokinetics of surface modified nanocarrier containing melphalan. Int J Pharm. 2012;426:219–30.
Chen Y, Chen C, Zheng J, Chen Z, Shi Q, Liu H. Development of a solid supersaturatable self-emulsifying drug delivery system of docetaxel with improved dissolution and bioavailability. Biol Pharm Bull. 2011;34:278–86.
Zhang T, Chen J, Zhang Y, Shen Q, Pan W. Characterization and evaluation of nanostructured lipid carrier as a vehicle for oral delivery of etoposide. Eur J Pharm Sci. 2011;43:174–9. Available:https://doi.org/10.1016/j.ejps.2011.04.005
Malam Y, Loizidou M, Seifalian AM. Liposomes and nanoparticles: Nanosized vehicles for drug delivery in cancer. Trends Pharmacol Sci. 2009;30: 592–9.