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.
Original language | English (US) |
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Article number | 965 |
Journal | Cancers |
Volume | 12 |
Issue number | 4 |
DOIs | |
State | Published - Apr 2020 |
Bibliographical note
Funding Information:Funding: Funding was provided by the Minnesota Ovarian Cancer Alliance Research Grant (S.P. and T.K.S.), the National Institute of Health (EB022558 to S.P.), the MN Masonic Cancer Center (TWG grant to T.K.S.), the Chorzempa Ovarian Cancer Research Fund (T.K.S.), and institutional grants to MCC from NIH/NCI P30CA07759821 and CTSI from NCATS UL1TR00249402.
Funding Information:
was provided by the Minnesota Ovarian Cancer Alliance Research Grant (S.P. and T.K.S.), the National Institute of Health (EB022558 to S.P.), the MN Masonic Cancer Center (TWG grant to T.K.S.), the Chorzempa Ovarian Cancer Research Fund (T.K.S.), and institutional grants to MCC from NIH/NCI P30CA07759821 and CTSI from NCATS UL1TR00249402. The authors sincerely thank Sundaram Ramakrishnan (Department of Surgery, University of Miami, Miami, FL, USA) for providing the C200 cell lines, the University Imaging Centers (UMN, Minneapolis) for assistance with live animal imaging, the Comparative Pathology Shared Resource (UMN, Minneapolis) for IHC workup and the University of Minnesota Genomics Center (UMGC) for their efforts and resources related to RT-PCR.
Publisher Copyright:
© 2020 by the authors. Licensee MDPI, Basel, Switzerland.
Keywords
- Cancer therapy
- Glycoengineering
- Mesenchymal stem cells
- Ovarian cancer
- Patient-derived xenograft tumor model
- Two-step tumor targeting
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