Bone metastasis targeting: A novel approach to reach bone using Zoledronate anchored PLGA nanoparticle as carrier system loaded with Docetaxel

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• 作者：Kiran Ramanlal Chaudhari^a ; ^b ; ^c ; Abhinesh Kumar^a ; Vinoth Kumar Megraj Khandelwal^b ; Mukesh Ukawala^a ; Arehalli S. Manjappa^a ; Anil Kumar Mishra^c ; Jukka Monkkonen^b ; Rayasa S. Ramachandra Murthy^d ; ^{m_rsr@rediffmail.com}
• 关键词：BPs ; Bisphosphonates ; ZOL ; Zoledronic acid ; DTX ; Docetaxel ; ApppI ; 1-adenosin-5&rsquo ; -yl ester 3-(3-methylbut-3-enyl) ester ; IPP ; Isopentenyl pyrophosphate ; PLGA ; Poly(lactide-Glycolide) acid ; NPs ; Nanoparticles ; 99mTc ; Technetium-99  ; m ; FPP synthase
• 刊名：Journal of Controlled Release
• 出版年：2012
• 期刊代码：25_01683659
• 类别：pha
• 出版时间：28 March, 2012
• 卷：158
• 期：3
• 页码：470-478
• 文件大小：1164 K

摘要

In spite of good research in drug delivery, bone targeting remains largely unexplored. Even some of the bone diseases are seldom cured just because of poor distribution of drug at the bone site. Zoledronate (ZOL) having strong affinity towards bone and its utility in bone metastasis management makes it perfect ligand for bone targeting. Recent studies revealed that ZOL in combination with docetaxel showed significant synergism in the management of bone metastasis. From the results, it is clear that ZOL-conjugated PLGA nanoparticles (NPs) showed more cellular uptake than pegylated PLGA NPs with change in cellular uptake route. In vitro studies on MCF-7 and BO2 cell line revealed that ZOL anchored PLGA-PEG NPs showed enhanced cell cytotoxicity, increase in cell cycle arrest and more apoptotic activity. PLGA-PEG-ZOL NPs found to block mevalonate pathway and increase accumulation of apoptotic metabolites such as ApppI. In vivo animal studies using technetium-99 m radiolabeling showed prolong blood circulation half-life, reduced liver uptake and significantly higher retention of ZOL tagged NPs at the bone site with enhanced tumor retention. Here, we can conclude that the targeting ability of ZOL enhanced by strong affinity to bone, enhanced endocytosis of ZOL anchored PLGA-PEG NPs.