In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 73, No. 8_Supplement ( 2013-04-15), p. 2154-2154
Abstract:
Bone metastasis targeting remains largely unexplored. Some of the bone diseases are seldom cured just because of poor distribution of drug to the bone. Zoledronic acid (ZOL) possess a strong affinity towards bone, and hence its utility in bone metastasis management makes it a perfect ligand for bone targeting. Recent studies revealed that ZOL in combination with docetaxel (DTX) showed significant synergism in the management of bone metastasis. DTX-loaded ZOL-conjugated polyethylene glycol (PEG)ylated polybutyl cyanoacrylate (PBCA) NPs (PBCA-PEG-ZOL) were prepared using the anionic polymerization technique. Physiochemical Characterization, pharmacokinetics, in vitro bone binding assay, quantitative cellular uptake, NP uptake route characterization, and cellular IPP/ApppI (isopentenyl pyrophosphate/triphosphoric acid 1-adenosin-5′-yl ester 3-(3-methylbut-3-enyl) ester) levels were performed. DTX was efficiently entrapped (75.94 ± 3.82%) in the Zol conjugated NPs, estimated by HPLC. They had discrete spherical shape, and size of around 82 nm estimated by zetasizer and transmission electron microscopy. Biodistribution studies using technetium-99m radiolabeling showed prolonged blood circulation half-life, and that the ratio of PBCA-PEG-ZOL NPs in tumor bearing bone to the normal bone was 3 fold, at any time point. Further, ZOL conjugated NPs localization in tumor bearing bone significantly increased with time and found to be 7.5 (p & lt;0.01), 20 (p & lt;0.001) and 155 (p & lt;0.001) times higher after 1, 4 and 24 h respectively, as compared with unconjugated but pegylated NPs, possibly due to the remodeling of the bone lining by tumor metastasis. In vitro bone binding assay using human simulated bone-hydroxyapatite powder results confirmed that ZOL has strong binding affinity to bone, and maintained the affinity even when used as a surface ligand conjugated to NPs. It was noticed that after 4 h of treatment with BO2 cells, ZOL conjugated NPs showed two times longer residence time (measured by flow cytometry) than un-conjugated ones. PBCA-PEG-ZOL NPs showed an enhanced cytotoxic effect (MTT assay) in both BO2 and MCF-7 cell lines, due to cell cycle arrest and apoptosis (by flow cytometry). Uptake route characterization studies (by confocal microscopy & flow cytometry) with different inhibitors revealed that PBCA-PEG-ZOL NPs uptake is not entirely based upon clathrin or caveolae mediated endocytosis. PBCA-PEG-ZOL NPs blocked the mevalonate pathway and showed 7 and 5.3 times increase in IPP and ApppI production (measured by Liquid chromatography-mass spectrometry; LC-MS), in comparison to ZOL treatment, and 138 times higher than the control group in MCF-7 cell line. These results provide evidence that ZOL-conjugated NPs provide an efficient and targeted delivery system for bone metastasis. Hence, these NPs present a promising treatment in the near future for bone related diseases. Citation Format: Vinoth Kumar Megraj Khandelwal, Kiran R. Chaudhari, Abhinesh Kumar, Anil K. Mishra, Jukka Monkkonen, Rayasa S. Ramachandra Murthy. Bone metastasis targeting: a novel approach to reach bone using zoledronate anchored nanoparticles loaded with docetaxel. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2154. doi:10.1158/1538-7445.AM2013-2154
Type of Medium:
Online Resource
ISSN:
0008-5472
,
1538-7445
DOI:
10.1158/1538-7445.AM2013-2154
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2013
detail.hit.zdb_id:
2036785-5
detail.hit.zdb_id:
1432-1
detail.hit.zdb_id:
410466-3
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