Bone Marrow-derived Mesenchymal Stem Cells (MSCs) as a Selective Delivery Vehicle for a PSA-Activated Protoxin for Advanced Prostate Cancer
Abstract
Circulating Mesenchymal Stem Cells (MSCs) originating from the bone marrow have the ability to differentiate into cells of the mesoderm lineage and an innate tropism for tumor tissue in response to the inflammatory microenvironment present in malignant lesions. MSCs have been detected in the perivascular space of many tumors, including those of the prostate, and have been shown to be a critical element in oncogenic progression. MSCs are inherently non-immunogenic, which prevents allogeneic MSCs from being rejected by normal host defense mechanisms. This immune-privileged status, together with their oncotropic properties, makes possible the infusion of allogeneic MSCs into patients for therapeutic purposes, such as the delivery of cytotoxic agents to sites of primary and metastatic prostate cancer. PRX302 is a PSA-activated aerolysin-based protoxin that forms membrane pores and leads to necrosis by a proliferation-independent mechanism at low picomolar concentrations. Importantly, PRX302 binds with low nanomolar affinity to GPI-anchor proteins, which are highly expressed on the surface of all mammalian cells. Therefore, MSCs can be genetically manipulated to express the PRX302 transgene endogenously from a safe harbor locus. Based upon this rationale we hypothesize that human bone marrow-derived mesenchymal stem cells (hMSCs) can be used as a cell-based targeting vehicle to selectively deliver therapeutic agents, such as PRX302, to primary and metastatic sites of prostate cancer, and thus spare host toxicity.
Document Details
- Document Type
- Technical Report
- Publication Date
- Mar 01, 2013
- Accession Number
- ADA580995
Entities
People
- William N. Brennen
Organizations
- Johns Hopkins University