Controlled Cisplatin Delivery Using pH-Sensitive PAA-Grafted Mesoporous Silica Nanoparticles

More than 70% of patients with ovarian cancer are diagnosed with metastasis, in which tumors spread to the peritoneal cavity. The current standards of care are intravenous (IV) or intraperitoneal (IP) injection of small-molecule anticancer drugs, such as cis-diamminedichloro platinum-(II) (cisplatin). Although IP injection enables delivery of higher drug concentrations to the tumor sites, the small molecules have low retention times. To overcome these challenges, we present two alternative nanoparticle-based formulations, namely, cisplatin-loaded dendritic mesoporous silica nanoparticles (Pt-MSNs) and poly-(acrylic acid) (PAA)-modified dendritic MSNs (Pt-PAA-MSNs). For both formulations, we obtained stable particles with uniform shapes/sizes that did not aggregate 15 days after in vitro drug release. We achieved loading amounts as high as 15% for Pt-MSNs and 18% for Pt-PAA-MSNs. PAA offers additional advantages such as a more sustained cisplatin release and a faster release in an acidic tumor environment due to the pH sensitivity of the polymer. The formulation showed a 4.8-times improvement in the half maximal inhibitory concentration (IC₅₀) against cancer cells. Pharmacokinetic (PK) studies further demonstrated an increased retention time of cisplatin in the peritoneal cavity, as absorbed Pt in the bloodstream reduced from 1.75 μg for free cisplatin (peaked as early as 30 min after IP injection) to 0.05 μg peaked at 300 min for Pt-PAA-MSNs. The biodistribution results in a metastasis-induced mouse model showed an increased accumulation of cisplatin in tumors of MSN-administered animals compared to those that received free cisplatin. These findings demonstrate the potential of Pt-PAA-MSNs as a promising platform for improving the efficacy and retention of cisplatin in peritoneal ovarian cancer treatment.