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 delivery 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 open chest procedure, systemic injection is safe but cannot get 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.