R01HL154154

Drug Delivery and Biomimetic Approaches for Optimal Stem Cell Therapy - Project Summary

Numerous studies indicate that adult stem cells exert their functional benefits mainly through paracrine effects, i.e., secreted factors from stem cells promote cardiac regeneration and inhibit fibrosis and inflammation. However, two major challenges remain to efficiently deliver stem cell factors to the injured myocardium:

1) Injected growth factors are quickly diffused, therefore sustained release is needed.
2) Local injection is effective but requires an open chest procedure, systemic injection is safe but cannot deliver a sufficient dosage to the heart, therefore targeted delivery is needed.

To overcome those challenges, we designed a platelet-inspired nano-cell (PINC) that has a core containing stem cell factors and a platelet membrane shell for injury binding. The core consists of therapeutic CSC-secreted factors encapsulated in a biodegradable poly (lactic-co-glycolic acid) (PLGA) nanoparticle for sustained release. The platelet membrane is conjugated with PGE2, which is expected to have targetability to cardiovascular cells and facilitate the endogenous repair through PGE2/EP receptor signaling after I/R injury.

As a novel biomimetic therapeutic nanoparticle, PINC offers the following advantages compared to natural stem cells:
(I) PINC is small enough for systemic administration: the nano size of PINC enables intravenous application; unlike stem cells, PINCs are less likely to be blocked by the lungs.
(II) PINC has dual targeting ability: the platelet membrane on PINCs targets injured blood vessels while the PGE2 targets injured cardiomyocytes in MI.
(III) PINC is stable during storage: unlike real stem cells, PINCs can be readily manipulated and cryopreserved since there are no living components.

The specific aims are:

Aim 1. Fabricate PINC particles functionalized with PGE2 and CSC secretome; test the in vitro potency and cytotoxicity of PINC.
Aim 2. Determine the safety, efficacy, and mechanism of PINC therapy in a rat model of ischemia-reperfusion (IR) injury.
Aim 3. Translate the findings into a clinically-relevant porcine model of IR injury.

Our study will form the foundation for an innovative and "off the shelf" therapy based on secreted factors and targeted nanomedicine that can be standardized from donor stem cell lines and xenogeneic cardiac tissues. The cell-free nature of our approach is more readily translatable to the clinic. Although this particular grant application targets the heart and cardiac stem cells, our approach represents a platform technology that can be applied to the creation of multiple types of synthetic stem cell and organ matrices for the repair of various other organs.

The Trustees Of Columbia University In The City Of New York

TO FOSTER HEART AND VASCULAR RESEARCH IN THE BASIC, TRANSLATIONAL, CLINICAL AND POPULATION SCIENCES, AND TO FOSTER TRAINING TO BUILD TALENTED YOUNG INVESTIGATORS IN THESE AREAS, FUNDED THROUGH COMPETITIVE RESEARCH TRAINING GRANTS. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM: TO STIMULATE TECHNOLOGICAL INNOVATION, USE SMALL BUSINESS TO MEET FEDERAL RESEARCH AND DEVELOPMENT NEEDS, FOSTER AND ENCOURAGE PARTICIPATION IN INNOVATION AND ENTREPRENEURSHIP BY SOCIALLY AND ECONOMICALLY DISADVANTAGED PERSONS, AND INCREASE PRIVATE-SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT FUNDING. SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM: TO STIMULATE TECHNOLOGICAL INNOVATION, FOSTER TECHNOLOGY TRANSFER THROUGH COOPERATIVE R&D BETWEEN SMALL BUSINESSES AND RESEARCH INSTITUTIONS, AND INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL R&D.

93.837 - Cardiovascular Diseases Research

National Heart Lung and Blood Institute (NHLBI) [HHS - NIH]

New York United States

State-Wide

Change of Recipient Organization (Type 7 Parent Clinical Trial Optional) (PA-21-268)

Amendment Since initial award the total obligations have increased 350% from $683,520 to $3,078,566.