DoE Based Optimization and Development of Spray-Dried Chitosan-Coated Alginate Microparticles Loaded with Cisplatin for the Treatment of Cervical Cancer

Page: [381 - 398] Pages: 18

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Abstract

Background: The existing parenteral treatment of cervical cancer has high toxicity and poor distribution of drugs at the targeted site.

Purpose: To formulate localized mucoadhesive cisplatin loaded microparticles based formulation to treat cervical cancer so that enhanced therapeutics benefits with low toxicity could be achieved.

Methods: Cisplatin loaded chitosan coated spray-dried microparticles were prepared by ionotropic gelation technique and optimized by Central Composite Design. The spray-dried uncoated and chitosan- coated microparticles were characterized for various parameters (Particle size, Morphology, Drug entrapment efficiency). In vitro drug release study was carried out in simulated vaginal fluids by dialysis membrane method. Ex vivo studies were carried out to evaluate the cytotoxic potential of the developed formulation by the MTT assay. A drug permeability study was performed by Franz diffusion cell using the vaginal tissue of Swiss Albino Mice.

Results: All in vitro characterization parameters were found to be optimum. The in vitro release studies indicated a controlled release following the Higuchi model. The chitosan-coated microparticles were found to be more cytotoxic than uncoated microparticles and plain cisplatin solution. The chitosan-coated microparticles were found to be more permeable than uncoated microparticles. Finally, in vivo tumor regression and histopathological studies confirmed the significant decrease in tumor volume at different time intervals.

Conclusion: Thus, it can be concluded that mucoadhesive spray-dried microparticles could provide a favorable approach for localized delivery of the anticancer drug via vaginal route against cervical cancer with its enhanced effectiveness.

Keywords: Cisplatin, cervical cancer, central composite design, localized drug delivery, microparticles, spray-dried microparticles.

Graphical Abstract

[1]
Jacob, M. Information, education & communication: Corner stone for preventing cancer of the cervix. Indian J. Med. Res., 2012, 136(2), 182-184.
[PMID: 22960883]
[2]
Ferlay, J.; Shin, H-R.; Bray, F.; Forman, D.; Mathers, C.; Parkin, D.M. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int. J. Cancer, 2010, 127(12), 2893-2917.
[http://dx.doi.org/10.1002/ijc.25516] [PMID: 21351269]
[3]
World Health Organisation. Comprehensive Cervical. Cancer Contr., 2006.
[4]
Arbyn, M.; Castellsagué, X.; de Sanjosé, S.; Bruni, L.; Saraiya, M.; Bray, F.; Ferlay, J. Worldwide burden of cervical cancer in 2008. Ann. Oncol., 2011, 22(12), 2675-2686.
[http://dx.doi.org/10.1093/annonc/mdr015] [PMID: 21471563]
[5]
Abedin-Do, A.; Taherian-Esfahani, Z.; Ghafouri-Fard, S.; Ghafouri-Fard, S.; Motevaseli, E. Immunomodulatory effects of Lactobacillus strains: emphasis on their effects on cancer cells. Immunotherapy, 2015, 7(12), 1307-1329.
[http://dx.doi.org/10.2217/imt.15.92] [PMID: 26595390]
[6]
Oun, R.; Moussa, Y.E.; Wheate, N.J. The side effects of platinum-based chemotherapy drugs: a review for chemists. Dalton Trans., 2018, 47(19), 6645-6653.
[http://dx.doi.org/10.1039/C8DT00838H] [PMID: 29632935]
[7]
Khurana, B.; Goyal, A.K.; Budhiraja, A.; Aora, D.; Vyas, S.P. Lipoplexes versus nanoparticles: pDNA/siRNA delivery. Drug Deliv., 2013, 20(2), 57-64.
[http://dx.doi.org/10.3109/10717544.2012.752419] [PMID: 23537464]
[8]
Illum, L. Chitosan and its use as a pharmaceutical excipient. Pharm. Res., 1998, 15(9), 1326-1331.
[http://dx.doi.org/10.1023/A:1011929016601] [PMID: 9755881]
[9]
Aggarwal, U.; Goyal, A.K.; Rath, G. Development and characterization of the cisplatin loaded nanofibers for the treatment of cervical cancer. Mater. Sci. Eng. C, 2017, 75, 125-132.
[http://dx.doi.org/10.1016/j.msec.2017.02.013] [PMID: 28415413]
[10]
Major, I.; McConville, C. Vaginal drug delivery for the localised treatment of cervical cancer. Drug Deliv. Transl. Res., 2017, 7(6), 817-828.
[http://dx.doi.org/10.1007/s13346-017-0395-2] [PMID: 28597123]
[11]
Onishi, H.; Koyama, K.; Sakata, O.; Machida, Y. Preparation of chitosan/alginate/calcium complex microparticles loaded with lactoferrin and their efficacy on carrageenan-induced edema in rats. Drug Dev. Ind. Pharm., 2010, 36(8), 879-884.
[http://dx.doi.org/10.3109/03639040903567109] [PMID: 20345284]
[12]
Jøraholmen, M.W.; Vanić, Z.; Tho, I.; Škalko-Basnet, N. Chitosan-coated liposomes for topical vaginal therapy: Assuring localized drug effect. Int. J. Pharm., 2014, 472(1-2), 94-101.
[http://dx.doi.org/10.1016/j.ijpharm.2014.06.016] [PMID: 24928137]
[13]
Learoyd, T.P.; Burrows, J.L.; French, E.; Seville, P.C. Chitosan-based spray-dried respirable powders for sustained delivery of terbutaline sulfate. Eur. J. Pharm. Biopharm., 2008, 68(2), 224-234.
[http://dx.doi.org/10.1016/j.ejpb.2007.04.017] [PMID: 17560772]
[14]
Shaji, J.; Shaikh, M. Formulation, Optimization, and Characterization of Biocompatible Inhalable D-Cycloserine-Loaded Alginate-Chitosan Nanoparticles for Pulmonary Drug Delivery. Asian J. Pharm. Clin. Res., 2016, 9, 82-95.
[http://dx.doi.org/10.22159/ajpcr.2016.v9s2.11814]
[15]
Meng, J.; Agrahari, V.; Ezoulin, M.J.; Purohit, S.S.; Zhang, T.; Molteni, A.; Dim, D.; Oyler, N.A.; Youan, B.C. Spray-Dried Thiolated Chitosan-Coated Sodium Alginate Multilayer Microparticles for Vaginal HIV Microbicide Delivery. AAPS J., 2017, 19(3), 692-702.
[http://dx.doi.org/10.1208/s12248-016-0007-y] [PMID: 28138910]
[16]
Sharma, A.; Arora, M.; Goyal, A.K.; Rath, G. Spray Dried Formulation of 5-Fluorouracil Embedded with Probiotic Biomass: In Vitro and In Vivo Studies. Probiotics Antimicrob. Proteins, 2017, 9(3), 310-322.
[http://dx.doi.org/10.1007/s12602-017-9258-x] [PMID: 28275899]
[17]
Kaushik, D.; Sharma, K.; Sardana, S. Colon Targeting Guar Gum Microspheres of 5-Aminosalicylic Acid: Evaluation of Various Process Variables, Characterization and in-Vitro Drug Release. Indian J. Pharm. Educ. Res., 2016, 50(2s), S106-S114.
[http://dx.doi.org/10.5530/ijper.50.2.25]
[18]
Ahmed, T.A.; Aljaeid, B.M. Preparation, characterization, and potential application of chitosan, chitosan derivatives, and chitosan metal nanoparticles in pharmaceutical drug delivery. Drug Des. Devel. Ther., 2016, 10, 483-507.
[http://dx.doi.org/10.2147/DDDT.S99651] [PMID: 26869768]
[19]
Arora, D.; Khurana, B.; Rath, G.; Nanda, S.; Goyal, A.K. Recent Advances in Nanosuspension Technology for Drug Delivery. Curr. Pharm. Des., 2018, 24(21), 2403-2415.
[http://dx.doi.org/10.2174/1381612824666180522100251] [PMID: 29788880]
[20]
Huh, S.J.; Liang, S.; Sharma, A.; Dong, C.; Robertson, G.P. Transiently entrapped circulating tumor cells interact with neutrophils to facilitate lung metastasis development. Cancer Res., 2010, 70(14), 6071-6082.
[http://dx.doi.org/10.1158/0008-5472.CAN-09-4442] [PMID: 20610626]
[21]
Quintana, A.; Raczka, E.; Piehler, L.; Lee, I.; Myc, A.; Majoros, I.; Patri, A.K.; Thomas, T.; Mule, J.; Baker, J.R. Design and Function of a Dendrimer-Based Therapeutic Nanodevice Targeted to Tumor Cells Through the Folate Receptor. Pharm Res., 2002, 19(9), 1310-1316.
[22]
Ravani, L.; Esposito, E.; Bories, C.; Moal, V.L.; Loiseau, P.M.; Djabourov, M.; Cortesi, R.; Bouchemal, K. Clotrimazole-loaded nanostructured lipid carrier hydrogels: thermal analysis and in vitro studies. Int. J. Pharm., 2013, 454(2), 695-702.
[http://dx.doi.org/10.1016/j.ijpharm.2013.06.015] [PMID: 23792467]
[23]
Dong, Z.; Zheng, W.; Xu, Z.; Yin, Z. Improved Stability and Tumor Targeting of 5-Fluorouracil by Conjugation with Hyaluronan. J. Appl. Polym. Sci., 2013, 130(2), 927-932.
[http://dx.doi.org/10.1002/app.39247]
[24]
Sunil, D.; Isloor, A.M.; Shetty, P.; Nayak, P.G.; Pai, K.S.R. In Vivo Anticancer and Histopathology Studies of Schiff Bases on Ehrlich Ascitic Carcinoma Cells. 1st Cancer Update. Arab. J. Chem., 2013, 6(1), 25-33.
[http://dx.doi.org/10.1016/j.arabjc.2010.12.016]
[25]
Zong, S.; Wang, X.; Yang, Y.; Wu, W.; Li, H.; Ma, Y.; Lin, W.; Sun, T.; Huang, Y.; Xie, Z.; Yue, Y.; Liu, S.; Jing, X. The use of cisplatin-loaded mucoadhesive nanofibers for local chemotherapy of cervical cancers in mice. Eur. J. Pharm. Biopharm., 2015, 93, 127-135.
[http://dx.doi.org/10.1016/j.ejpb.2015.03.029] [PMID: 25843238]
[26]
Arora, D.; Khurana, B.; Kumar, M.S.; Vyas, S.P. Oral Immunization against Hepatitis B Virus Using. Int. J. Recent Adv. Pharm. Res., 2011, 1, 45-51.
[27]
Arora, D.; Khurana, B.; Narang, R.K.; Nanda, S. Quality by Design (QbD) Approach for Optimization and Development of Nano Drug Delivery Systems. Trends Drug Deliv., 2016, 3(3), 23-32.
[28]
Gupta, N.V.; Natasha, S.; Getyala, A.; Bhat, R.S. Bioadhesive vaginal tablets containing spray dried microspheres loaded with clotrimazole for treatment of vaginal candidiasis. Acta Pharm., 2013, 63(3), 359-372.
[http://dx.doi.org/10.2478/acph-2013-0027] [PMID: 24152896]
[29]
Pahal, S.; Arora, D.; Kumar, M.S.; Mahadevan, N. Development of Paclitaxel Loaded Immunonanoparticles for HER-2 Positive Breast Cancer Cells. Int. J. Recent Adv. Pharm. Res., 2011, 1, 25-39.