Department of Biomedical Engineering
Labhasetwar’s Laboratory in Nanomedicine
Neuroprotective Nanoparticles for treating CNS injuries: We began investigating the efficacy of unique neuroprotective nanoparticles in CNS injuries, particularly in stroke and spinal cord injury. We recently expanded my research into the area of blast wave-associated traumatic brain injury (bTBI), a significant issue for the military. Our overall therapeutic strategy is to inhibit the progression of the secondary injury cascades of degenerative events that follow the primary injury and promote the endogenous brain-repair mechanisms. Our recent and ongoing studies have demonstrated that delivery of neuroprotective nanoparticles at the time of reperfusion in a stroke model is effective in minimizing the damage due to ischemia/reperfusion injury, leading to neuronal regeneration and functional recovery over time. We are now expanding our research to other types of CNS injuries.
- Reddy MK, Labhasetwar V. Nanoparticle-mediated delivery of superoxide dismutase to the brain: an effective strategy to reduce ischemia-reperfusion injury. FASEB J 2009;23:1384-95.
- Hayder J, Adjei, Labhasetwar V. Optical imaging to map the blood-brain barrier leakage. Sci Rep. 2013 Nov 1;3:3117. doi: 10.1038/srep03117.
- Singhal A, Morris VB, Labhasetwar V, Ghorpade A. Nanoparticle-mediated catalase delivery protects human neurons from oxidative stress. Cell Death Dis 2013;4:e903. PMCID: PMC3847304.
- Kabu S, Jaffer H, Petro M, Dudzinski D, Stewart D, Courtney A, Courtney M, Labhasetwar V. Blast-associated shock waves result in increased brain vascular leakage and elevated ROS levels in a rat model of traumatic brain injury. PLoS One 2015;10:e0127971. PMCID: PMC4449023
- Petro M, Jaffer H, Yang J, Kabu S, Morris VB, Labhasetwar V. Tissue plasminogen activator followed by antioxidant-loaded nanoparticle delivery promotes activation/mobilization of progenitor cells. Biomaterials 2016, 81, 169-180.
Epigenetic cancer nanotherapy and cancer drug resistance/metastasis: We have been studying nanoparticles for cancer nanomedicine, particularly as a drug-/gene-delivery system to overcome resistance to chemotherapy drugs. Our laboratory’s recent focus has been on understanding the role of epigenetic changes in cancer drug resistance and tumor metastasis. In this regard, we have been investigating epigenetic nanotherapy for treating resistant and metastatic breast tumors. We are also examining the role of epigenetics in breast cancer stem cells and testing the approach of reprogramming them with epigenetic drugs to make them more susceptible to conventional anticancer drugs.
- Peetla C, Bhave R, Vijayaraghavalu S, Stine A, Kooijman E, Labhasetwar V. Drug resistance in breast cancer cells: Biophysical characterization of and doxorubicin interactions with membrane lipids. Mol Pharmaceutics 2010;7:2334-48. PMCID: PMC2997943
- Prabha S, Sharma B, Labhasetwar V. Inhibition of tumor angiogenesis and growth by nanoparticle-mediated p53 gene therapy in mice. Cancer Gene Ther 2012;19:530-7. PMCID: PMC3400709
- Vijayaraghavalu S, Labhasetwar V. Efficacy of decitabine-loaded nanogels in overcoming cancer drug resistance is mediated via sustained DNA methyl transferase 1 (DNMT1) depletion. Cancer Lett 2013;331:122-9. PMCID: PMC3572331
- Vijayaraghavalu S, Peetla C, Lu S, Labhasetwar V. Epigenetic modulation of the biophysical properties of drug-resistant cell lipids to restore drug transport and endocytic functions. Mol Pharmaceutics 2012;9:2730-42. PMCID: PMC3433581
- Adjei IM, Sharma B, Peetla C, Labhasetwar V3. Inhibition of bone loss with surface-modulated, drug-loaded nanoparticles in an intraosseous model of prostate cancer. J Controlled Release 2016; 232, 83–92. PMID: 27090164
Cellular uptake and intracellular trafficking of nanoparticles: My laboratory has extensively investigated the mechanism of cellular uptake of nanoparticles (NPs) and their intracellular trafficking. We first discovered that poly lactic co-glycolic acid (PLGA) NPs rapidly escape endosomes following their cellular uptake, but in our subsequent studies, we found that only a small fraction of the internalized NPs escape endosomes and are retained by cells. A major fraction (85%) of these internalized NPs remains in recycling endosomes and undergoes exocytosis. This observation led us to further studies to understand the role of NP surface characteristics on cellular uptake, endosomal escape, and retention.
- Panyam J, Zhou WZ, Prabha S, Sahoo SK, Labhasetwar V. Rapid endo-lysosomal escape of poly(d,l-lactide-co-glycolide) nanoparticles: implications for drug and gene delivery. FASEB J 2002;16:1217-26.
- Panyam J, Labhasetwar V. Dynamics of endocytosis and exocytosis of poly(d,l-lactide-co-glycolide) nanoparticles in vascular smooth muscle cells. Pharm Res 2003;20:212-20.
- Vasir JK, Labhasetwar V. Quantification of the force of nanoparticle-cell membrane interactions and its influence on intracellular trafficking of nanoparticles. Biomaterials 2008;29:4244-52. PMCID: PMC2570224
- Morris VB, Labhasetwar V. Arginine-rich polyplexes for gene delivery to neuronal cells. Biomaterials 2015, 60, 151-160.
Role of biophysics of membrane lipids in drug delivery: We found that biophysical interactions of nanoparticles (NPs) depend on both biophysical (e.g., membrane fluidity) properties of membrane lipids and NP characteristics (interfacial properties). Recently, we determined that biomechanics (bending force) and thermodynamics (“Gibbs free energy”) of interactions of NPs with cell membrane lipids play an important role in endocytosis and escape of NPs from endosomes. We also found that selective biophysical interaction of NPs with the membrane lipids of cancer cells vs. normal cells could be developed as a new targeting approach for drug/gene delivery.
- Peetla C, Labhasetwar V. Effect of molecular structure of cationic surfactants on biophysical interactions of surfactant-modified nanoparticles with a model membrane and cellular uptake. Langmuir 2009;25:2369–77. PMCID: PMC2653596
- Sharma B, Peetla C, Adjei IM, Labhasetwar V. Selective biophysical interactions of surface modified nanoparticles with cancer cell lipids improve tumor targeting and gene therapy. Cancer Lett 2013;334:228-36. PMCID: PMC3669664
- Peetla C, Vijayaraghavalu S, Labhasetwar V. Biophysics of cell membrane lipids in cancer drug resistance: Implications for drug transport and drug delivery with nanoparticles. Adv Drug Deliv Rev 2013;65:1686-98. PMCID: PMC3840112
- Peetla C, Jin S, Weimer J, Elegbede A, Labhasetwar V. Biomechanics and thermodynamics of nanoparticle interactions with plasma and endosomal membrane lipids in cellular uptake and endosomal escape. Langmuir 2014;30:7522-32. PMCID: PMC4079324