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The effect of drug loading and multiple administration on the protein corona formation and brain delivery property of PEG-PLA nanoparticles

Institution:	1. Department of Pharmacology and Chemical Biology, Shanghai Universities Collaborative Innovation Center for Translational Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China;2. Department of Geriatric Psychiatry, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Alzheimer''s Disease and Related Disorder Center, Shanghai Jiao Tong University, Shanghai 200025, China;3. Institute of Interdisciplinary Integrative Biomedical Research, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 201210, China

Abstract:	The presence of protein corona on the surface of nanoparticles modulates their physiological interactions such as cellular association and targeting property. It has been shown that α-mangostin (αM)-loaded poly(ethylene glycol)-poly(l-lactide) (PEG-PLA) nanoparticles (NP-αM) specifically increased low density lipoprotein receptor (LDLR) expression in microglia and improved clearance of amyloid beta (Aβ) after multiple administration. However, how do the nanoparticles cross the blood?brain barrier and access microglia remain unknown. Here, we studied the brain delivery property of PEG-PLA nanoparticles under different conditions, finding that the nanoparticles exhibited higher brain transport efficiency and microglia uptake efficiency after αM loading and multiple administration. To reveal the mechanism, we performed proteomic analysis to characterize the composition of protein corona formed under various conditions, finding that both drug loading and multiple dosing affect the composition of protein corona and subsequently influence the cellular uptake of nanoparticles in b.End3 and BV-2 cells. Complement proteins, immunoglobulins, RAB5A and CD36 were found to be enriched in the corona and associated with the process of nanoparticles uptake. Collectively, we bring a mechanistic understanding about the modulator role of protein corona on targeted drug delivery, and provide theoretical basis for engineering brain or microglia-specific targeted delivery system.

Keywords:	Protein corona Nanoparticles Brain delivery Microglia PEG-PLA amyloid beta BBB"} {"#name":"keyword" "$":{"id":"kwrd0060"} "$$":[{"#name":"text" "_":"blood?brain barrier CNS"} {"#name":"keyword" "$":{"id":"kwrd0070"} "$$":[{"#name":"text" "_":"central nervous system cou6"} {"#name":"keyword" "$":{"id":"kwrd0080"} "$$":[{"#name":"text" "_":"coumarin 6 cou6-NPs"} {"#name":"keyword" "$":{"id":"kwrd0090"} "$$":[{"#name":"text" "_":"cou6-labeled nanoparticles cou7"} {"#name":"keyword" "$":{"id":"kwrd0100"} "$$":[{"#name":"text" "_":"coumarin 7 DLS"} {"#name":"keyword" "$":{"id":"kwrd0110"} "$$":[{"#name":"text" "_":"dynamic light scattering HCS"} {"#name":"keyword" "$":{"id":"kwrd0120"} "$$":[{"#name":"text" "_":"high content screening LDLR"} {"#name":"keyword" "$":{"id":"kwrd0130"} "$$":[{"#name":"text" "_":"low density lipoprotein receptor MCI"} {"#name":"keyword" "$":{"id":"kwrd0140"} "$$":[{"#name":"text" "_":"mild cognitive impairment NP"} {"#name":"keyword" "$":{"id":"kwrd0150"} "$$":[{"#name":"text" "_":"blank PEG-PLA nanoparticles NP-corona complexes"} {"#name":"keyword" "$":{"id":"kwrd0170"} "$$":[{"#name":"text" "_":"nanoparticle-corona complexes PEG-PLA"} {"#name":"keyword" "$":{"id":"kwrd0180"} "$$":[{"#name":"text" "$$":[{"#name":"__text__" "_":"poly(ethylene glycol)–poly("} {"#name":"small-caps" "_":"l"} {"#name":"__text__" "_":"-lactide) TEER"} {"#name":"keyword" "$":{"id":"kwrd0190"} "$$":[{"#name":"text" "_":"trans-epithelial electrical resistance TEM"} {"#name":"keyword" "$":{"id":"kwrd0200"} "$$":[{"#name":"text" "_":"transmission electronic microscope
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