(M1430-01-05) Cisplatin-Loaded Dendritic Mesoporous Silica Nanoparticles for Improved Drug Delivery to Ovarian Cancer Metastasis

Purpose: Greater than 70% of ovarian cancer patients are diagnosed with metastasis characterized by the spread of tumors to the peritoneal cavity. The present protocol for treating ovarian cancer involves administering small-molecule anticancer drugs, such as cisplatin, through intravenous (IV) or intraperitoneal (IP) injection. Despite the ability of intraperitoneal (IP) injection to deliver higher drug concentrations to tumor sites, small molecules exhibit poor retention times. In order to address these issues, we developed a novel cisplatin-loaded polyacrylic acid (PAA) modified dendritic mesoporous silica nanoparticles (Pt-PAA-MSNs).

Methods: Dendritic MSNs were synthesized by oil-water biphase stratification method. Amine functionalized dendritic MSNs were further reacted with PAA to obtain PAA-MSNs. Cisplatin loading through subsequent reaction was carried to obtain Pt-PAA-MSNs. These nanoparticles were characterized for their physicochemical properties like size, morphology, zeta potential using Transmission Electron Microscopy (TEM) and Dynamic Light Scattering (DLS) techniques. Polymer attachment was investigated by Fourier-transform infrared spectroscopy (FTIR) and Thermogravimetric analysis (TGA). The elemental composition of different samples was measured by Inductively Couple Plasma-Optical Emission Spectroscopy (ICP-OES). An infinite microplate reader was used to calculate cell viability. Animal studies in nude mice bearing human ovarian cancer OVCAR-8 in the peritoneal cavity were conducted for understanding the pharmacokinetic (PK) profile and biodistribution of the nanoparticles

Results: We attained stable particles with consistent shapes and sizes that remained unaggregated even after 15 days following drug release in an in vitro environment (Figure 1). Cisplatin loading capacity of 18% was successfully achieved for Pt-PAA-MSNs. Due to the pH-sensitive nature of PAA, Pt-PAA-MSNs showed facilitated release of cisplatin in the acidic tumor microenvironment while avoiding its release in systemic circulation, enabling the prolonged release profile of cisplatin. The formulation demonstrated a 4.8-fold enhancement in the half-maximal inhibitory concentration (IC50) against cancer cells. PK investigations revealed an extended retention period of cisplatin within the peritoneal cavity, with a decline in absorbed Pt in the bloodstream from 1.75 μg for free cisplatin, with a peak as early as 30 minutes after IP injection, compared to 0.05 μg peaked at 300 minutes for Pt-PAA-MSNs. Biodistribution results in metastasis-induced mouse model showed 2 times increase in accumulation of cisplatin in tumors 24h post administration of Pt-PAA-MSNs compared to those received free cisplatin.

Conclusion: The developed cisplatin loaded dendritic MSNs exhibited favorable drug carrying and tumor delivery properties and demonstrated the potential for the treatment of metastatic ovarian cancer.

TEM images of Pt-PAA-MSN in acetate buffer with pH=5.2 after 15 days of release