Journal
JOURNAL OF CONTROLLED RELEASE
Volume 270, Issue -, Pages 158-176Publisher
ELSEVIER
DOI: 10.1016/j.jconrel.2017.11.045
Keywords
CD38; Bortezomib; Endocytosis; Nanoparticles, multiple myeloma
Funding
- Multiple Myeloma Research Foundation (MMRF) Research Fellow Award
- National Center for Advancing Translational Sciences (NCATS) of the National Institutes of Health (NIH)
- National Cancer Institute (NCI) of the NIH [U54CA199092]
- NATIONAL CANCER INSTITUTE [U54CA199092] Funding Source: NIH RePORTER
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The establishment of more effective treatments that can circumvent chemoresistance in Multiple Myeloma (MM) is a priority. Although bortezomib (BTZ) is one of the most potent proteasome inhibitors available, still possesses limitations related to dose limiting side effects. Several strategies have been developed to improve the delivery of chemotherapies to MM by targeting different moieties expressed on MM cells to nanoparticle delivery systems (NPs), which have failed mainly due to their heterogeneous expression on these cells. Our goal was to test CD38 targeted chitosan NPs as novel targeting moiety for MM to improve the potency and efficacy of BTZ in MM cells and reduce the side effects in healthy tissue. We have showed preferential BTZ release in tumor-micro-environment, specific binding to MM cells, and an improved drug cellular uptake through BTZ diffusion from the surface and endocytosed NPs, which translated in enhanced proteasome inhibition and robust cytotoxic effect on MM cells when BTZ was administered through anti-CD38 chitosan NPs. Furthermore, the anti-CD38 chitosan NPs specifically delivered therapeutic agents to MM cells improving therapeutic efficacy and reducing side effects in vivo. The anti-CD38 chitosan NPs showed low toxicity profile allowing enhancement of proteasome-inhibitory activity and specificity of BTZ by endocytosis-mediated uptake of CD38 representing a promising therapy in MM.
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