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Anti-Cancer Agents in Medicinal Chemistry


ISSN (Print): 1871-5206
ISSN (Online): 1875-5992

Research Article

Design, Synthesis and Studies on Novel Polymeric Prodrugs of Erlotinib for Colon Drug Delivery

Author(s): Sahil Kumar, Bandna Sharma, Tilak R. Bhardwaj and Rajesh K. Singh*

Volume 21 , Issue 3 , 2021

Published on: 11 August, 2020

Page: [383 - 392] Pages: 10

DOI: 10.2174/1871520620666200811124013

Price: $65


Aims: In the present study, polymer-drug conjugates were synthesized based on azo-bond cleavage drug delivery approach for targeting erlotinib as an anticancer drug specifically to the colon for the proficient treatment of colon cancer.

Background: Colon Cancer (CC) is the third commonly detected tumor worldwide and makes up about 10% of all cases of cancers. Most of the chemotherapeutic drugs available for treating colon cancer are not only toxic to cancerous cells but also to the normal healthy cells. Among the various approaches to get rid of the adverse effects of anticancer agents, prodrugs are one of the most imperative approaches.

Objective: The objective of the study is to chemically modify the erlotinib drug through azo-bond linkage and suitable spacer which will be finally linked to the polymeric backbone to give the desired polymer linked prodrug. The azo reductase enzyme present in the colon is supposed to cleave the azo-bond specifically and augment the drug release at the colon.

Methods: The synthesized conjugates were characterized by IR and 1H-NMR spectroscopy. The cleavage of aromatic azo-bond resulted in a potential colon-specific liberation of drug from conjugate studied in rat fecal contents. In vitro release profiles of polyphosphazene-linked conjugates of erlotinib have been studied at pH 1.2, pH 6.8 and pH 7.4. The stability study was designed to exhibit that free drug was released proficiently and unmodified from polyphosphazene-erlotinib conjugates having aromatic azo-bond in artificial colon conditions.

Results: The synthesized conjugates were demonstrated to be stable in simulated upper gastrointestinal tract conditions. The drug release kinetics shows that all the polymer-drug conjugates of erlotinib follow zero-order release kinetics which indicates that the drug release from the polymeric backbone is independent of its concentration. Kinetic study of conjugates with slope (n) shows the anomalous type of release with an exponent (n) > 0.89 indicating a super case II type of release.

Conclusion: These studies indicate that polyphosphazene linked drug conjugates of erlotinib could be promising candidates for the site-specific treatment of colon cancer with the least detrimental side-effects.

Keywords: Polymer, polymer-drug conjugates, polyphosphazene-erlotinib conjugates, erlotinib, drug-conjugates, colon cancer.

Graphical Abstract
Forman, D. Chapter 1.1: The global and regional burden of cancer. In: Stewart BW, Wild CP (eds.). World Cancer Report. The International Agency for Research on Cancer; World Health Organization, 2014; pp. 16-53.
Bray, F.; Ferlay, J.; Soerjomataram, I.; Siegel, R.L.; Torre, L.A.; Jemal, A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries CA. Cancer J. Clinic., 2018, 68(6), 394-424.
Bosman, F.T. Colorectal Cancer.In: World Cancer Report. The International Agency for Research on Cancer, World Health Organization; Stewart, B.W.; Wild, C.P., Eds.; , 2014, pp. 392-402.
Risio, M. The natural history of adenomas. Best Pract. Res. Clin. Gastroenterol., 2010, 24, 271-280.
Winawer, S.J.; Zauber, A.G. The advanced adenoma as the primary target of screening. Gastrointest. Endosc. Clin. N. Am., 2002, 12(1), 1-9.
[] [PMID: 11916153]
Levine, J.S.; Ahnen, D.J. Clinical practice. Adenomatous polyps of the colon. N. Engl. J. Med., 2006, 355(24), 2551-2557.
[] [PMID: 17167138]
Schatzkin, A.; Freedman, L.S.; Dawsey, S.M.; Lanza, E. Interpreting precursor studies: What polyp trials tell us about large-bowel cancer. J. Natl. Cancer Inst., 1994, 86(14), 1053-1057.
[] [PMID: 7802771]
Bond, J.H. Practice Parameters Committee of the American College of Gastroenterology. Polyp guideline: Diagnosis, treatment, and surveillance for patients with colorectal polyps. Am. J. Gastroenterol., 2000, 95(11), 3053-3063.
[] [PMID: 11095318]
Colon Cancer Treatment (PDQ), National Cancer Institute, Available 34 at:
Dahan, A.; Khamis, M.; Agbaria, R.; Karaman, R. Targeted prodrugs in oral drug delivery: The modern molecular biopharmaceutical approach. Expert Opin. Drug Deliv., 2012, 9(8), 1001-1013.
[] [PMID: 22703376]
Lakshmi, S.; Katti, D.S.; Laurencin, C.T. Biodegradable polyphosphazenes for drug delivery applications. Adv. Drug Deliv. Rev., 2003, 55(4), 467-482.
[] [PMID: 12706046]
Neilson, R.H.; Neilson, P.W. Poly(alkyl/arylphosphazenes) and their precursors. Chem. Rev., 1988, 88, 541-562.
Teasdale, I.; Brüggemann, O. Polyphosphazenes: Multifunctional, biodegradable vehicles for drug and gene delivery. Polymers (Basel), 2013, 5(1), 161-187.
[] [PMID: 24729871]
Schacht, E.; Gevaert, A.; Kenawy, E.R.; Molly, K.; Verstaete, W. Polymers for colon specific drug delivery. J. Control. Release, 1996, 39, 327-338.
Zou, M.J.; Cheng, G.; Okamoto, H.; Hao, X.H.; An, F.; Cui, F.D.; Danjo, K. Colon-specific drug delivery systems based on cyclodextrin prodrugs: in vivo evaluation of 5-aminosalicylic acid from its cyclodextrin conjugates. World J. Gastroenterol., 2005, 11(47), 7457-7460.
[] [PMID: 16437716]
Jung, Y.; Kim, H.H.; Kim, H.; Kong, H.; Choi, B.; Yang, Y.; Kim, Y. Evaluation of 5-aminosalicyltaurine as a colon-specific prodrug of 5-aminosalicylic acid for the treatment of experimental colitis. Eur. J. Pharm., 2006, 28(1-2), 26-33.
Smith, H.W. Observations on the flora of the alimentary tract of animals and factors affecting its composition. J. Pathol. Bacteriol., 1965, 89, 95-122.
[] [PMID: 14263502]
Rubinstein, A. Microbially controlled drug delivery to the colon. Biopharm. Drug Dispos., 1990, 11(6), 465-475.
[] [PMID: 2207298]
Schellekens, R.C.A.; Stuurman, F.E.; van der Weert, F.H.J.; Kosterink, J.G.W.; Frijlink, H.W. A novel dissolution method relevant to intestinal release behaviour and its application in the evaluation of modified release mesalazine products. Eur. J. Pharm. Sci., 2007, 30(1), 15-20.
[] [PMID: 17085024]
Dhaneshwar, S.S.; Gairola, N.; Kandpal, M.; Vadnerkar, G.; Bhatt, L.; Rathi, B.; Kadam, S.S. Synthesis, kinetic studies and pharmacological evaluation of mutual azo prodrugs of 5-aminosalicylic acid for colon-specific drug delivery in inflammatory bowel disease. Eur. J. Med. Chem., 2009, 44(10), 3922-3929.
[] [PMID: 19442419]
Kumari, A.; Singh, R.K. Morpholine as ubiquitous pharmacophore in medicinal chemistry: Deep insight into the Structure-Activity Relationship (SAR). Bioorg. Chem., 2020, 96103578
[]] [PMID: 31978684]
Sethi, N.; Prasad, D.N.; Singh, R.K. An insight into the synthesis and Structure-Activity Relationship (SAR) of 2,4-thiazolidinedione (2,4-TZD): A review. Mini Rev. Med. Chem., 2020, 20, 308.
[] [PMID: 31660809]
Kumari, A.; Singh, R.K. Medicinal chemistry of indole derivatives: Current to future therapeutic prospectives. Bioorg. Chem., 2019, 89103021
[]] [PMID: 31176854]
Townsley, C.A.; Major, P.; Siu, L.L.; Dancey, J.; Chen, E.; Pond, G.R.; Nicklee, T.; Ho, J.; Hedley, D.; Tsao, M.; Moore, M.J.; Oza, A.M. Phase II study of erlotinib (OSI-774) in patients with metastatic colorectal cancer. Br. J. Cancer, 2006, 94(8), 1136-1143.
[] [PMID: 16570047]
Pagán, B.; Isidro, A.A.; Cruz, M.L.; Ren, Y.; Coppola, D.; Wu, J.; Appleyard, C.B. Erlotinib inhibits progression to dysplasia in a colitis-associated colon cancer model. World J. Gastroenterol., 2011, 17(44), 4858-4866.
[] [PMID: 22171126]
Shen, T.; Cheng, X.; Xia, C.; Li, Q.; Gao, Y.; Pan, D.; Zhang, X.; Zhang, C.; Li, Y. Erlotinib inhibits colon cancer metastasis through inactivation of TrkB-dependent ERK signaling pathway. J. Cell. Biochem., 2019, 120, 11248-11255.
[] [PMID: 30719765]
Kumar, S.; Singh, R.K.; Murthy, R.S.R.; Bhardwaj, T.R. Synthesis and evaluation of substituted poly(organophosphazenes) as a novel nanocarrier system for combined antimalarial therapy of primaquine and dihydroartemisinin. Pharm. Res., 2015, 32(8), 2736-2752.
[] [PMID: 25777611]
Kumar, S.; Singh, R.K.; Sharma, R.; Murthy, R.S.R.; Bhardwaj, T.R. Design, synthesis and evaluation of antimalarial potential of polyphosphazene linked combination therapy of primaquine and dihydroartemisinin. Eur. J. Pharm. Sci., 2015, 66, 123-137.
[] [PMID: 25312346]
Kumar, S.; Singh, R.K.; Prasad, D.N.; Bhardwaj, T.R. Synthesis of novel controlled molecular weight substituted poly(organophosphazenes): Synthesis, characterization and in vitro degradation studies. J. Drug Deliv. Sci. Technol., 2017, 38, 135-142.
Kumar, S.; Sharma, B.; Thakur, K.; Bhardwaj, T.R.; Prasad, D.N.; Singh, R.K. Recent advances in the development of polymeric nanocarrier formulations for the treatment of colon cancer. Drug Deliv. Lett., 2019, 9, 2-14.
Sharma, R.; Rawal, R.K.; Gaba, T.; Singla, N.; Malhotra, M.; Matharoo, S.; Bhardwaj, T.R. Design, synthesis and ex vivo evaluation of colon-specific azo based prodrugs of anticancer agents. Bioorg. Med. Chem. Lett., 2013, 23(19), 5332-5338.
[] [PMID: 23968824]
Singh, R.K.; Kumar, S.; Prasad, D.N.; Bhardwaj, T.R. Therapeutic journery of nitrogen mustard as alkylating anticancer agents: Historic to future perspectives. Eur. J. Med. Chem., 2018, 151, 401-433.
[] [PMID: 29649739]
Singh, R.K.; Prasad, D.N.; Bhardwaj, T.R. Design, synthesis, chemical and biological evaluation of brain targeted alkylating agent using reversible redox prodrug approach. Arab. J. Chem., 2017, 10, 420-429.
Singh, R.K.; Prasad, D.N.; Bhardwaj, T.R. Design, synthesis and antiproliferative activity of benzodiazepine-mustard conjugates as potential brain antitumour agents. J. Saudi Chem. Soc., 2017, 21, S86-S93.
Singh, R.K.; Prasad, D.N.; Bhardwaj, T.R. Hybrid pharmacophore-based drug design, synthesis and antiproliferative activity of 1,4-dihydropyridines linked alkylating anticancer agents. Med. Chem. Res., 2015, 24, 1534-1541.
Singh, R.K.; Prasad, D.N.; Bhardwaj, T.R. Synthesis, physicochemical and kinetic studies of redox derivative of bis(2-chloroethylamine) as alkylating cytotoxic agent for brain delivery. Arab. J. Chem., 2015, 8, 380-387.
Singh, R.K.; Kumar, S.; Prasad, D.N.; Bhardwaj, T.R. Reversible redox system based drug design for targeting alkylating agent across brain. Med. Chem. Res., 2014, 23, 2405-2416.
Singh, R.K.; Prasad, D.N.; Bhardwaj, T.R. Synthesis, in vitro/in vivo evaluation and in silico physicochemical study of prodrug approach for brain targeting of alkylating agent. Med. Chem. Res., 2013, 22, 5324-5336.
Singh, R.K.; Prasad, D.N.; Bhardwaj, T.R. Design, synthesis and evaluation of aminobenzophenone derivatives containing nitrogen mustard moiety as potential CNS antitumour agents. Med. Chem. Res., 2013, 22, 5901-5911.
Singh, R.K.; Prasad, D.N.; Bhardwaj, T.R. Synthesis, alkylation activity and physicochemical evaluation of nitrogen mustard agent to penetrate the blood-brain barrier. Asian J. Chem., 2012, 24, 5605-5608.
Chakravarthy, V.A.; Sailaja, B.B.V. Method development and validation of uv-visible spectroscopic method for the estimation of assay of anticancer drugs- axitinib, bosutinib, erlotinibhydrochloride, gefitinib and pemetrexed disodium drugs in API form. Eur. J. Pharm. Med. Res., 2016, 3, 609-624.
Allcock, H.R. Chemistry and applications of polyphosphazenes. J. Am. Chem. Soc., 2003, 125, 9539-9540.
Allcock, H.R. The synthesis of functional polyphosphazenes and their surfaces. Appl. Organomet. Chem., 1998, 12, 659-666.
Gudasi, K.B.; Vadavi, R.S.; Sreedhar, B.; Sairam, M.N.; Shelke, B.; Mallikarjuna, N.N.; Kulkarni, P.V.; Aminahbavi, T.M. Synthesis and characterization of some organopolyphosphazenes and their controlled-release characteristics. Des. Monomers Polym., 2007, 10, 235-251.
Mohammad, A.U.; Mohammed, M. Design and synthesis of azo derivatives of 5-fluorouacil for targeting colon cancer. J. Ad. Chem., 2014, 7, 2456-2459.
Dolezal, M.; Miletin, M.; Kunes, J.; Kralova, K. Substituted amide of pyrazine-2-carboxylic acids: Synthesis and biological activity. Molecules, 2002, 7, 363-373.
Hardcastle, J.D.; Chamberlain, J.O.; Robinson, M.H.; Moss, S.M.; Amar, S.S.; Balfour, T.W.; James, P.D.; Mangham, C.M. Randomised controlled trial of faecal-occult-blood screening for colorectal cancer. Lancet, 1996, 348(9040), 1472-1477.
[] [PMID: 8942775]
Sharma, A.; Dhiman, S.; Arora, S.; Chand, P.; Kapoor, A. Synthesis of colon specific N, N- bis-(2-chloroethyl) aniline polyphosphazene copolymer conjugates. Int. J. Pharm. Pharm. Sci., 2010, 2, 975-1491.
Fukui, E.; Miyamura, N.; Uemura, K.; Kobayashi, M. Preparation of enteric coated timed-release press-coated tablets and evaluation of their function by in vitro and in vivo tests for colon targeting. Int. J. Pharm., 2000, 204(1-2), 7-15.
[] [PMID: 11011980]
Rudolph, M.W.; Klein, S.; Beckert, T.E.; Petereit, H.; Dressman, J.B. A new 5-aminosalicylic acid multi-unit dosage form for the therapy of ulcerative colitis. Eur. J. Pharm. Biopharm., 2001, 51(3), 183-190.
[] [PMID: 11343881]
Sharma, M.; Malik, R.; Verma, A.; Dwivedi, P.; Banoth, G.S.; Pandey, N.; Sarkar, J.; Mishra, P.R.; Dwivedi, A.K. Folic acid conjugated guar gum nanoparticles for targeting methotrexate to colon cancer. J. Biomed. Nanotechnol., 2013, 9(1), 96-106.
[] [PMID: 23627072]
Uekama, K.; Minami, K.; Hirayama, F. 6A-O-[(4-Biphenylyl)acetyl]-r-, -â-, and -γ-cyclodextrins and 6A-Deoxy-6A-[[(4-biphenylyl)acetyl]amino]-r-, -â-, and -γ-cyclodextrins: Potential prodrugs for colon-specific delivery. J. Med. Chem., 1997, 40, 2755-2761.
[] [PMID: 9276021]
Marslin, G.; Sheeba, C.J.; Kalaichelvan, V.K.; Manavalan, R.; Reddy, P.N.; Franklin, G. Poly(D,L-lactic-co-glycolic acid) nanoencapsulation reduces Erlotinib-induced subacute toxicity in rat. J. Biomed. Nanotechnol., 2009, 5(5), 464-471.
[] [PMID: 20201419]
Dash, S.; Murthy, P.N.; Nath, L.; Chowdhury, P. Kinetic modeling on drug release from controlled drug delivery systems. Acta Pol. Pharm., 2010, 67(3), 217-223.
[PMID: 20524422]
Ferdous, R.; Anisuzzaman, S.M.; Paul, A.K.; Khan, M.S.; Begum, A.A.; Kundu, S.K. In vitro release kinetic study of gliclazide from methocel k 100 mcr and methocel k100 lvcr matrix tablets. Int. J. Pharm. Tech. Res., 2012, 4, 883-888.

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