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.
Highlights
Ovarian cancer is one of the fatal female diseases in which many patients are diagnosed at an advanced stage when the disease has already spread beyond the ovaries to the abdominal cavity [1,2,3]
Our findings showed that plasma MUC16 antigen levels were consistent with tumor growth, ascitic fluid development and mouse survival with distinct and combination chemo-treatments, indicative of MUC16 as a valuable biomarker to investigate the effect of chemo-therapeutic interventions on epithelial ovarian cancer (EOC) in Athymic Swiss mice
The present study has demonstrated for the first time that combining anti-MUC16 antibodies with drug-loaded nanomicellles in a hydrogel composite can inhibit intra-peritoneal tumor growth, reducing the consequent production of ascites, resulting in increased survival rate of the Athymic Swiss nude mouse model
Summary
Ovarian cancer is one of the fatal female diseases in which many patients are diagnosed at an advanced stage when the disease has already spread beyond the ovaries to the abdominal cavity [1,2,3]. Targeted chemotherapy has been a considerable advancement compared to passive-targeting based on the Enhanced Permeability and Retention (EPR) effect To this end, actively targeted chemotherapeutic drug delivery employing nanotechnology has had a remarkable impact on cancer treatment with the following advantages: (1) Ability to deliver antineoplastic drugs to treat specific cancer metastatic sites; (2) potential reduction in the quantity of drug necessary to achieve a required therapeutic dose at the target cancer tissue; and (3) reduction in the quantity of drug delivered to healthy cells decreasing cell cytotoxicity [4,5,6]. This ensures active targeting nanomicelle preparation without any steric-hindrance for the ligand-antibody [9,10]
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