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.
