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Intracellular Trafficking of Nanoparticles The endo-lysosomal escape of drug carriers is crucial to enhancing the efficacy of their macromolecular payload, especially the payloads that are susceptible to lysosomal degradation. Current vectors that enable the endo-lysosomal escape of macromolecules such as DNA are limited by their toxicity and by their ability to carry only limited classes of therapeutic agents. In this paper, we report the rapid (<10 min) endo-lysosomal escape of biodegradable nanoparticles (NPs) formulated from the copolymers of poly(DL-lactide-co-glycolide) (PLGA). The mechanism of rapid escape is by selective reversal of the surface charge of NPs (from anionic to cationic) in the acidic endo-lysosomal compartment, which causes the NPs to interact with the endo-lysosomal membrane and escape into the cytosol. PLGA NPs are able to deliver a variety of therapeutic agents, including macromolecules such as DNA and low molecular weight drugs such as dexamethasone, intracellularly at a slow rate, which results in a sustained therapeutic effect.
Angiogenesis therapy
The concept of therapeutic angiogenesis in the treatment of ischemic diseases has evolved from the discovery of several polypeptide growth factors that augment the development of collateral blood vessels. However, the success of angiogenesis therapy is currently hindered by the lack of an optimal delivery strategy that would provide sustained and localized levels of proangiogenic growth factors in the diseased tissue. We are investigating nanospheres as a delivery system for vascular endothelial growth factor (VEGF), a potent proangiogenic agent. Nanospheres encapsulating VEGF demonstrates sustained release of biologically active VEGF. VEGF-loaded nanospheres demonstrate greater and more sustained effects on endothelial cell proliferation, migration, and morphogenesis in vitro as compared to the protein in solution. Therefore, nanospheres could be an effective system for the sustained localized delivery of VEGF and other proangiogenic growth factors to achieve therapeutic angiogenesis in the ischemic tissue.
Restenosis therapy
Restenosis, the re-obstruction of an artery following an interventional procedure such as balloon angioplasty, remains a major limitation to the success of these interventional procedures. Proliferation of the normally quiescent vascular smooth muscle cells is considered as the most critical step in the development of restenosis. This proliferation occurs in response to a variety of endogenous cytokines that are released after the injury caused by the intervention. Hence, a sustained inhibition of the vascular smooth muscle cell proliferation would allow re-endothelialization of the injured artery, and hence would be expected to inhibit restenosis. For such sustained inhibition, it is important to maintain therapeutic concentration of the active agent at the site of injury. The localized arterial delivery of biodegradable nanoparticles offers the possibility of such site-specific sustained delivery of antiproliferative agents. We are also investigating polymeric micellar nanosystems for the localized intra-arterial delivery of water insoluble antiproliferative agents
Fig 2b: Inhibition of restenosis with drug loaded nanoparticles
Gene Therapy
We are investigating nanoparticles formulated from biodegradable polymers such as poly (lactic acid) and poly (lactide-co-glycolide) (PLGA) as a non-viral gene delivery system. We are investigating various parameters affecting the transfection efficacy of PLGA nanoparticles. This system has demonstrated sustained gene expression both in vitro and in vivo. Current projects include investigation of p53, a tumor suppressor gene, loaded nanoparticles for prostate and breast cancer.
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