Pantshwa, Jonathan M.Rhoda, KhadijaClift, Sarah JanePradeep, PriyamvadaChoonara, Yahya E.Kumar, PradeepDu Toit, Lisa C.Penny, ClementPillay, VinessPillay, Viness2018-12-142018-12-142018-10-04Pantshwa, J.M., Rhoda, K., Clift, S.J. et al. 2018, 'Chemotherapeutic efficacy of implantable antineoplastic-treatment protocols in an optimal mouse model for human ovarian carcinoma cell targeting', International Journal of Molecular Sciences, vol. 19, no. 10, art. 3030, pp. 1-27.1422-0067 (online)10.3390/ijms19103030http://hdl.handle.net/2263/68105The present study aimed to design and develop a nanocomposite drug delivery system employing an antineoplastic-loaded antibody functionalized nanomicelle encapsulated within a Chitosan–Poly(vinylpyrrolidone)–Poly(N-isopropylacrylamide) (C–P–N) hydrogel to form an in situ forming implant (ISFI), responsive to temperature and pH for cancer cell-targeting following intraperitoneal implantation. The optimum nanomicelle formulation was surface-functionalized with anti-MUC 16 (antibody) for the targeted delivery of methotrexate to human ovarian carcinoma (NIH:OVCAR-5) cells in Athymic nude mice that expressed MUC16, as a preferential form of intraperitoneal ovarian cancer (OC) chemotherapy. The cross-linked interpenetrating C–P–N hydrogel was synthesized for the preparation of an in situ-forming implant (ISFI). Subsequently, the ISFI was fabricated by encapsulating a nanocomposite comprising of anti-MUC16 (antibody) functionalized methotrexate (MTX)-loaded poly(N-isopropylacrylamide)-b-poly(aspartic acid) (PNIPAAm-b-PASP) nanomicelles (AF(MTX)NM’s) within the cross-linked C–P–N hydrogel. This strategy enabled specificity and increased the residence time of the nanomicelles at tumor sites over a period exceeding one month, enhancing uptake of drugs and preventing recurrence and chemo-resistance. Chemotherapeutic efficacy was tested on the optimal ovarian tumor-bearing Athymic nude mouse model and the results demonstrated tumor regression including reduction in mouse weight and tumor size, as well as a significant (p < 0.05) reduction in mucin 16 levels in plasma and ascitic fluid, and improved survival of mice after treatment with the experimental anti-MUC16/CA125 antibody-bound nanotherapeutic implant drug delivery system (ISFI) (p < 0.05). The study also concluded that ISFI could potentially be considered an important immuno-chemotherapeutic agent that could be employed in human clinical trials of advanced, and/or recurring, metastatic epithelial ovarian cancer (EOC). The development of this ISFI may circumvent the treatment flaws experienced with conventional systemic therapies, effectively manage recurrent disease and ultimately prolong disease-free intervals in ovarian cancer patients.en© 2018 by the authors; licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution license (http://creativecommons.org/licenses/by/4.0/).ImplantAntibody functionalized nanomicellesEpithelial ovarian cancerChemotherapeutic drugsNude mouse modelDrug deliveryMonoclonal antibody (MAb)Polymeric micellesControlled releaseAntitumor activityAnticancer drugPaclitaxelNanoparticlesCombinationArticle