Collaborative Project # 6: Tumor Targeted Drug Delivery Nanoplatform to Overcome Therapy Resistance Glioblastoma 

Collaborating Investigator: Alfredo Quinones-Hinojosa, MD 
Affiliation: Mayo Clinic, Florida   

Funding Source: NIH
Grant Number: R01NS129671
Project Period: 12/01/22-11/30/27  

Significance

Mesenchymal stem cells, like immune cells, show great promise as engineering targets for subsequent cellular therapy. However, they also face the same challenges, namely the need for a safe and effective non-viral enabling technology for precise genetic engineering. In CP #6, the Quinones-Hinojosa lab will collaborate with the NCBIB to apply our large library of nanoparticles to the challenge of ex vivo stem cell engineering. These engineered cells will then be investigated for varied applications, including the treatment of brain cancer. 

Approach

Aim 1: Evaluate NIM nanoparticles for ex vivo engineering of human mesenchymal stem cells (hMSCs).  hMSCs have great potential as cellular therapeutics, including for autologous or allogenic use. Ex vivo cellular engineering of them can enable the cells to secrete therapeutic proteins useful for treating cancer and other diseases. NIMs from TR&D2 Specific Aim 1 with a variety of chemical and physical properties will be evaluated for high DNA delivery efficacy, low cytotoxicity, and for not altering MSC phenotype following transfection.

Aim 2: Utilize leading NIMs from Aim 1 to deliver DNA encoding anti-cancer secretable proteins to hMSCs to treat brain cancer.  Lead NIM particles from Aim 1 will be loaded with DNA encoding TRAIL and bone morphogenic protein 4 (BMP4) to evaluate the ability for hMSCs to secrete these proteins and to trigger anti-glioma activity. hMSCs will be evaluated in vitro and then subsequently evaluated in vivo in glioma mouse models.

Push-Pull relationship:

Push: JH-TIE is developing tools for cellular engineering of hard-to-transfect cells; it is a natural extension to leverage this technology to other cell types to enable cell therapy. The Center has an interest in discovering how to best use these materials for hMSC transfection, which has utility for regenerative immunology as well as new directions of cancer therapy.

Pull: Viral gene therapy strategies have safety and manufacturing concerns, and an effective, safe, scalable nanoparticle system for hMSC engineering is greatly desired by Dr. Quinones-Hinojosa and coworkers at the Mayo Clinic. Dr. Quinones’ lab is eager to evaluate the materials in human mesenchymal stem cells to understand the potential robustness of the materials as a platform for cell therapy. Upon finding an optimized polymer for their needs, they are interested in evaluation of the engineered cells in animal models.    

TRD