Chemotherapeutic efficacy of implantable antineoplastic-treatment protocols in an optimal mouse model for human ovarian carcinoma cell targeting
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Date
Authors
Pantshwa, Jonathan M.
Rhoda, Khadija
Clift, Sarah Jane
Pradeep, Priyamvada
Choonara, Yahya E.
Kumar, Pradeep
Du Toit, Lisa C.
Penny, Clement
Pillay, Viness
Pillay, Viness
Journal Title
Journal ISSN
Volume Title
Publisher
MDPI Publishing
Abstract
The 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.
Description
Keywords
Implant, Antibody functionalized nanomicelles, Epithelial ovarian cancer, Chemotherapeutic drugs, Nude mouse model, Drug delivery, Monoclonal antibody (MAb), Polymeric micelles, Controlled release, Antitumor activity, Anticancer drug, Paclitaxel, Nanoparticles, Combination
Sustainable Development Goals
Citation
Pantshwa, 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.