Chondroitin sulfate conjugation facilitates tumor cell internalization of albumin nanoparticles for brain-targeted deliv
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ORIGINAL ARTICLE
Chondroitin sulfate conjugation facilitates tumor cell internalization of albumin nanoparticles for brain-targeted delivery of temozolomide via CD44 receptor-mediated targeting Ritu R. Kudarha 1 & Krutika K. Sawant 1 Accepted: 17 September 2020 # Controlled Release Society 2020
Abstract In the present investigation, temozolomide (TMZ) loaded chondroitin sulfate conjugated albumin nanoparticles (CS-TNPs) were fabricated by desolvation method were chondroitin sulfate (CS) was used as the surface exposed ligand to achieve CD44 receptor mediated targeting of brain tumor. The developed CS-TNPs were characterized for particle size, zeta potential, entrapment efficiency and drug loading and evaluated by FTIR, DSC, XRD and TEM analysis. BBB (blood brain barrier) passage study using in vitro BBB model indicated that CS-TNPs were able to efficiently cross the BBB. Cell viability assay data demonstrated higher cytotoxicity of CS-TNPs as compared with pure TMZ. The CD44 receptor blocking assay and receptor poisoning assay in U87 MG cells confirmed the CD44 receptor and endocytosis-mediated (caveolae pathway) uptake of CS-TNPs. CS-TNPs were able to generate ROS in U87 MG cells. In vivo pharmacokinetic and biodistribution studies were performed in Wistar rats. In vivo results revealed significant enhancement in pharmacokinetic profile of CS-TNPs as compared with TMZ alone. Biodistribution results demonstrated higher accumulation of TMZ in the brain by CS-TNPs as compared with the pure drug that confirmed the brain targeting ability of nanoparticles. From all obtained results, it may be concluded that CS-TNPs are promising carrier to deliver TMZ to the brain for targeted therapy of brain tumor. Keywords BSA nanoparticles . Chondroitin sulfate . Temozolomide . Brain targeting . CD44 blocking assay . Toxicity and Stability study
Introduction Temozolomide (TMZ) is a first-line drug used for the treatment of brain tumors. It is basically an alkylating agent and a prodrug which firstly gets converted into highly unstable compound 5-(3-methyltriazen-1-yl) imidazole-4-carboxamide (MTIC) at physiological pH and then MTIC is further converted into 5-aminoimidazole-4-carboxamide (AIC) and methyldiazonium ion. Formation of these methyldiazonium ions causes breakage of double strand of DNA and leads to cell cycle arrest and cell death by methylation of DNA [1]. Although TMZ has the ability to cross the blood brain barrier
* Krutika K. Sawant [email protected] 1
Drug Delivery Research Laboratory, Centre of Relevance and Excellence in NDDS, Faculty of Pharmacy, The Maharaja Sayajirao University of Baroda, Donor’s Plaza, Fathegunj, Vadodara 390002, India
(BBB), it needs a high systemic dose to reach a therapeutic concentration in the brain because of its short half-life. Due to this, various systemic side effects like oral ulceration, bone marrow suppression, fatigue, vomiting, nausea, and headache are associated with TMZ therapy [2, 3]. To overcome these side effects and to improve its therapeutic activity
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