Polymeric Nanoparticle-Mediated Gene Delivery to Human Astrocytes
| dc.contributor.author | Labhasetwar, Vinod | |
| dc.contributor.author | Ghorpade, Anuja | |
| dc.creator | Joshi, Chaitanya | |
| dc.date.accessioned | 2019-08-22T20:05:28Z | |
| dc.date.available | 2019-08-22T20:05:28Z | |
| dc.date.issued | 2017-03-16 | |
| dc.date.submitted | 2017-02-23T13:57:06-08:00 | |
| dc.description.abstract | Purpose: Astrocyte tissue-inhibitor of metalloproteinases-1 (TIMP-1) protects neurons during HIV-1-induced apoptosis. However, TIMP-1 levels decrease during chronic inflammation typical of HIV-associated neurocognitive disorders (HAND). We propose that astrocyte-targeted TIMP-1-gene delivery could be a suitable therapeutic for HAND. Nanoparticle (NP)-mediated gene delivery is a viable approach since genes can be delivered to specific brain cell types and NPs are less immunogenic than viral vectors. To test this hypothesis, obtaining a safe and effective gene delivery system is essential. Methods: We tested the gene delivery potential of arginine-based polyethylenimine (PEI) analogs (AnPn) and poly-lactic-co-glycolic-acid (PLGA) in vitro (primary human cells) and in vivo (mice) using a luciferase-reporter plasmid (pLuc). Immunocytochemisty and immunohistochemistry were carried out using antibodies specific to glial fibrillary acidic protein (GFAP), microtubule-associated protein 2 (MAP2), and luciferase. Results: PLGA NPs delivered pLuc across astrocyte plasma membrane but failed to induce protein expression. In parallel, A5P50, a PEI analog, efficiently expressed pLuc in astrocytes. Yet, its neuronal biocompatibility was not optimal. Combining low doses of AnPn with pLuc-loaded-PLGA NPs lead to high gene expression in all cell types including astrocytes. Live imaging indicated that AnPn facilitated PLGA-released-pLuc delivery across the nuclear membrane by an unknown mechanism. Consequently, optimally biocompatible PEI analogs were also synthesized and tested. Conclusions: Our data indicate that AnPn-PLGA combination and new AnPn analogs overcome both neuronal biocompatibility and astrocyte-specific gene expression issues promising clinical translations for HAND treatment in future. | |
| dc.identifier.uri | https://hdl.handle.net/20.500.12503/27765 | |
| dc.language.iso | en | |
| dc.provenance.legacyDownloads | 0 | |
| dc.title | Polymeric Nanoparticle-Mediated Gene Delivery to Human Astrocytes | |
| dc.type | poster | |
| dc.type.material | text |