Mesenchymal Stem Cells As Guideposts for Nanoparticle-Mediated Targeted Drug Delivery in Ovarian Cancer
Buddhadev Layek, Mihir Shetty, Susheel Kumar Nethi, Drishti Sehgal, Timothy K. Starr, Swayam Prabha
Abstract
Nanocarriers have been extensively utilized for the systemic targeting of various solid tumors and their metastases. However, current drug delivery systems, in general, suffer from a lack of selectivity for tumor cells. Here, we develop a novel two-step targeting strategy that relies on the selective accumulation of targetable synthetic receptors (i.e., azide moieties) in tumor tissues, followed by delivery of drug-loaded nanoparticles having a high binding affinity for these receptors. Mesenchymal stem cells (MSCs) were used as vehicles for the tumor-specific accumulation of azide moieties, while dibenzyl cyclooctyne (DBCO) was used as the targeting ligand. Biodistribution and antitumor efficacy studies were performed in both orthotopic metastatic and patient-derived xenograft (PDX) tumor models of ovarian cancer. Our studies show that nanoparticles are retained in tumors at a significantly higher concentration in mice that received azide-labeled MSCs (MSC-Az). Furthermore, we observed significantly reduced tumor growth (p < 0.05) and improved survival in mice receiving MSC-Az along with paclitaxel-loaded DBCO-functionalized nanoparticles compared to controls. These studies demonstrate the feasibility of a two-step targeting strategy for efficient delivery of concentrated chemotherapy for treating solid tumors.