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Optimization of Inositol Hexaphosphate Colon Targeted Formulation for Anticarcinogenic Marker Modulation

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Abstract

Colorectal cancer has become the third most frequent reason of cancer death in men and women. Currently, natural compounds are being looked up to, for subversion and deterrence of cancers. Inositol hexaphosphate (IP6) is one such naturally occurring phosphorylated carbohydrate present in most legumes and cereals which acts as a potential antineoplastic agent and can be used effectively to prevent and treat colon carcinomas. Despite the immense potential, due to the prevalence of high charge and ability to form salts and chelates with various divalent metals, it gets excreted out quickly from the body. On reaching the colon in its original form, it can serve as an effective anticancer agent. Therefore, a suitable dosage form that can prevent the drugs from being absorbed from the upper gastrointestinal tract is required to be prepared, to target it to the colon. Thus, microspheres of IP6 using a biodegradable polymer that degrades in the colon were attempted using the solvent evaporation method. The formulation was investigated for percentage yield, encapsulation efficiency, particle size distribution modification, and release rate. Optimized formulation showed particle size of 92 ± 0.76 μm, entrapment efficiency of 67.26% ± 0.75, percent drug loading of 15.74%, and in vitro drug release 82.36 ± 0.51. The results of the in vivo study divulged that IP6 loaded pectin microspheres showed significant positive modulation of biomarker levels and restoration of colonic architecture to almost normal as observed through histopathology and scanning electron microscopy studies in DMH-induced colon tumors in Albino Wistar rats.

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References

  1. Sirohi B, Shrikhande SV, Perakath B, Raghunandharao D, Julka PK, Lele V, et al. Indian Council of Medical Research consensus document for the management of colorectal cancer. Indian J Med Paediatr Oncol. 2014;35(3):192–6.

    PubMed  PubMed Central  Google Scholar 

  2. Matejuk A, Shamsuddin A. IP6 in cancer therapy: past, present and future. Curr Canc Ther Rev. 2010;6(1):1–12.

    CAS  Google Scholar 

  3. Graf E, Eaton JW. Suppression of colonic cancer by dietary phytic acid. Nutr Cancer. 1993;19(1):11–9.

    CAS  PubMed  Google Scholar 

  4. Shamsuddin A. Phytate and colon-cancer risk. Am J Clin Nutr. 1992;55(2):478.

    CAS  PubMed  Google Scholar 

  5. Thompson LU, Zhang L. Phytic acid and minerals: effect on early markers of risk for mammary and colon carcinogenesis. Carcinogenesis. 1991;12(11):2041–5.

    CAS  PubMed  Google Scholar 

  6. Gani A, Wani S, Masoodi F, Hameed G. Whole-grain cereal bioactive compounds and their health benefits: a review. J Food Process Technol. 2012;3(3):146–56.

    Google Scholar 

  7. Corpet DE, Pierre F. Point: from animal models to prevention of colon cancer. Systematic review of chemoprevention in min mice and choice of the model system. Cancer Epidemiol Biomark Prev. 2003;12(5):391–400.

    Google Scholar 

  8. Weglarz L, Parfiniewicz B, Orchel A, Dzierzewicz Z. Anti-proliferative effects of inositol hexaphosphate and verapamil on human colon cancer Caco-2 and HT-29 cells. Acta Pol Pharm. 2006;63:443–5.

    CAS  PubMed  Google Scholar 

  9. Liu G, Song Y, Cui L, Wen Z, Lu X. Inositol hexaphosphate suppresses growth and induces apoptosis in HT-29 colorectal cancer cells in culture: PI3K/Akt pathway as a potential target. Int J Clin Exp Pathol. 2015;8(2):1402–10.

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Rizvi I, Riggs DR, Jackson BJ, Ng A, Cunningham C, Mcfadden DW. Inositol hexaphosphate (IP6) inhibits cellular proliferation in melanoma. J Surg Res. 2006;133(1):3–6.

    CAS  PubMed  Google Scholar 

  11. Shamsuddin AM. Inositol phosphates have novel anticancer function. J Nutr. 1995;125(suppl_3):725S–32S.

    CAS  PubMed  Google Scholar 

  12. Kalam Shamsuddin A, Bose S. IP6 (inositol hexaphosphate) as a signaling molecule. Curr Signal Transduct Ther. 2012;7(3):289–304.

    Google Scholar 

  13. Philip AK, Philip B. Colon targeted drug delivery systems: a review on primary and novel approaches. Oman Medical Journal. 2010;25(2):79–87.

    PubMed  PubMed Central  Google Scholar 

  14. Paharia A, Yadav AK, Rai G, Jain SK, Pancholi SS, Agrawal GP. Eudragit-coated pectin microspheres of 5-fluorouracil for colon targeting. AAPS PharmSciTech. 2007;8(1):E87–93.

    PubMed Central  Google Scholar 

  15. Prasanth V, Moy AC, Mathew ST, Mathapan R. Microspheres—an overview. Int J Res Pharmaceut Biomed Sci. 2011;2(2):332–8.

    Google Scholar 

  16. Lee BK, Yun Y, Park K. PLA micro- and nano-particles. Adv Drug Deliv Rev. 2016;107:176–91.

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Xing L, Dawei C, Liping X, Rongqing Z. Oral colon-specific drug delivery for bee venom peptide: development of a coated calcium alginate gel beads-entrapped liposome. J Control Release. 2003;93(3):293–300.

    PubMed  Google Scholar 

  18. Kutmalge M, Ratnaparkhi M, Wattamwar M, Chaudhari S. A review on microsphere. Pharma Science Monitor. 2014;5.

  19. Lee C-M, Kim D-W, Lee H-C, Lee K-Y. Pectin microspheres for oral colon delivery: preparation using spray drying method and in vitro release of indomethacin. Biotechnol Bioprocess Eng. 2004;9(3):191–5.

    CAS  Google Scholar 

  20. Pawan C, Hemchand P. Magnetic microsphere: as targeted drug delivery. J Pharm Res. 2009;2:5.

    Google Scholar 

  21. Tao SL, Desai TA. Microfabricated drug delivery systems: from particles to pores. Adv Drug Deliv Rev. 2003;55(3):315–28.

    CAS  PubMed  Google Scholar 

  22. Anuar ST, Ithurayasamy PN, Rose LC. Exploiting fatty acid-polymer-based lauric acid and chitosan as coating material for drug encapsulation. Middle-East J Sci Res. 2016;24(63):2116–22.

    CAS  Google Scholar 

  23. Kumbhar DM, Mali KK, Dias RJ, Havaldar VD, Ghorpade VS, Salunkhe NH. Formulation and development of ethyl cellulose coated pectin based capecitabine loaded microspheres for colorectal cancer. RJPDFT. 2016;8(4):261.

    Google Scholar 

  24. Jain A, Khare P, Agrawal RK, Jain SK. Metronidazole loaded pectin microspheres for colon targeting. J Pharm Sci. 2009;98(11):4229–36.

    PubMed  Google Scholar 

  25. Esposito E, Cortesi R, Luca G, Nastruzzi C. Pectin-based microspheres: a preformulatory study. Ann N Y Acad Sci. 2001;944(1):160–79.

    CAS  PubMed  Google Scholar 

  26. Arya M, Singh P, Tripathi CB, Parashar P, Singh M, Kanoujia J, et al. Pectin-encrusted gold nanocomposites containing phytic acid and jacalin: 1,2-dimethylhydrazine-induced colon carcinogenesis in Wistar rats, PI3K/Akt, COX-2, and serum metabolomics as potential targets. Drug Deliv Transl Res. 2019;9(1):53–65.

    CAS  PubMed  Google Scholar 

  27. Parashar P, Tripathi CB, Arya M, Kanoujia J, Singh M, Yadav A, et al. A facile approach for fabricating CD44-targeted delivery of hyaluronic acid-functionalized PCL nanoparticles in urethane-induced lung cancer: Bcl-2, MMP-9, caspase-9, and BAX as potential markers. Drug Deliv Transl Res. 2019;9(1):37–52.

    CAS  PubMed  Google Scholar 

  28. Gaur PK, Mishra S, Bajpai M. Formulation and evaluation of controlled-release of telmisartan microspheres: in vitro/in vivo study. J Food Drug Anal. 2014;22(4):542–8.

    CAS  PubMed  Google Scholar 

  29. Ghosh MS. Formulation and evaluation of hydroxyzine hydrochloride sustained release microspheres by ionotropic gelation technique using Carbopol 934P. Asian J Pharm. 2014;8(4):230–6.

    CAS  Google Scholar 

  30. Jain N, Gulati N, Kumar D, Nagaich U. Microspheres: mucoadhesion based controlled drug delivery system. RGUHS J Pharm Sci. 2012;2(3):28–40.

    Google Scholar 

  31. Potu A, Pasunooti S, Veerareddy P, Burra S. Formulation and evaluation of fenoprofen calcium compressed coated tablets for colon specific drug delivery. Asian J Pharm Clin Res. 2011;4(2):88–95.

    CAS  Google Scholar 

  32. Vaidya A, Jain S, Agrawal RK, Jain SK. Pectin–metronidazole prodrug bearing microspheres for colon targeting. J Saudi Chem Soc. 2015;19(3):257–64.

    Google Scholar 

  33. Trivedi P, Verma A, Garud N. Preparation and characterization of aceclofenac microspheres. Asian J Pharm. 2014;2:2.

    Google Scholar 

  34. Wakerly Z, Fell JT, Attwood D, Parkins DA. In vitro evaluation of pectin-based colonic drug delivery systems. Int J Pharm. 1996;129(1–2):73–7.

    CAS  Google Scholar 

  35. Yadav A, Mote H. Development of biodegradable starch microspheres for intranasal delivery. Indian J Pharm Sci. 2008;70(2):170–4.

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Soppimath K, Kulkarni A, Aminabhavi T. Encapsulation of antihypertensive drugs in cellulose-based matrix microspheres: characterization and release kinetics of microspheres and tableted microspheres. J Microencapsul. 2001;18(3):397–409.

    CAS  PubMed  Google Scholar 

  37. Haug W, Lantzsch HJ. Sensitive method for the rapid determination of phytate in cereals and cereal products. J Sci Food Agric. 1983;34(12):1423–6.

    CAS  Google Scholar 

  38. Camire A, Clydesdale F. Analysis of phytic acid in foods by HPLC. J Food Sci. 1982;47(2):575–8.

    CAS  Google Scholar 

  39. Harland BF, Smikle-Williams S, Oberleas D. High performance liquid chromatography analysis of phytate (IP6) in selected foods. J Food Compos Anal. 2004;17(2):227–33.

    CAS  Google Scholar 

  40. Arya M, Tiwari P, Tripathi CB, Parashar P, Singh M, Sinha P, et al. Colloidal vesicular system of inositol hexaphosphate to counteract DMBA induced dysregulation of markers pertaining to cellular proliferation/differentiation and inflammation of epidermal layer in mouse model. Mol Pharm. 2017;14(3):928–39.

    CAS  PubMed  Google Scholar 

  41. Bird RP. Observation and quantification of aberrant crypts in the murine colon treated with a colon carcinogen: preliminary findings. Cancer Lett. 1987;37(2):147–51.

    CAS  PubMed  Google Scholar 

  42. Mishra RK, Sammi SR, Rawat JK, Roy S, Singh M, Gautam S, et al. Palonosetron attenuates 1,2-dimethyl hydrazine induced preneoplastic colon damage through downregulating acetylcholinesterase expression and up-regulating synaptic acetylcholine concentration. RSC Adv. 2016;6(46):40527–38.

    CAS  Google Scholar 

  43. Kaithwas G, Majumdar DK. In vitro antioxidant and in vivo antidiabetic, antihyperlipidemic activity of linseed oil against streptozotocin-induced toxicity in albino rats. Eur J Lipid Sci Technol. 2012;114(11):1237–45.

    CAS  Google Scholar 

  44. Neufert C, Becker C, Neurath MF. An inducible mouse model of colon carcinogenesis for the analysis of sporadic and inflammation-driven tumor progression. Nat Protoc. 2007;2:1998–2004.

    CAS  PubMed  Google Scholar 

  45. Pandey M, Gupta KP. Epigenetics, an early event in the modulation of gene expression by inositol hexaphosphate in ethylnitrosourea exposed mouse lungs. Nutr Cancer. 2011;63(1):89–99.

    CAS  PubMed  Google Scholar 

  46. Lachman L, Lieberman HA, Kanig JL. The theory and practice of industrial pharmacy: Lea & Febiger Philadelphia; 1976.

  47. Guideline IHT. Stability testing of new drug substances and products. Q1A (R2), current step, vol. 4; 2003. p. 1–24.

    Google Scholar 

  48. Rosenberg DW, Giardina C, Tanaka T. Mouse models for the study of colon carcinogenesis. Carcinogenesis. 2008;30(2):183–96.

    PubMed  PubMed Central  Google Scholar 

  49. Prasad VG, Kawade S, Jayashree B, Reddy ND, Francis A, Nayak PG, et al. Iminoflavones combat 1,2-dimethyl hydrazine-induced aberrant crypt foci development in colon cancer. Biomed Res Int. 2014;2014:1–7.

    Google Scholar 

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Acknowledgments

The authors are grateful to Babasaheb Bhimrao Ambedkar University (BBAU), Lucknow, India, for providing the necessary infrastructure, research laboratory, and support during the course of the research study. We are thankful to ICMR (Ref. no.74/1/2017-Pers (EMS)) for the JRF to NM, and EMS to KPG.

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Correspondence to Shubhini A. Saraf.

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Mishra, N., Arya, M., Gupta, K.P. et al. Optimization of Inositol Hexaphosphate Colon Targeted Formulation for Anticarcinogenic Marker Modulation. AAPS PharmSciTech 20, 319 (2019). https://doi.org/10.1208/s12249-019-1529-2

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