Metastasis targeting: a novel approach to reach bone using zoledronate anchored nanoparticles
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Metastasis targeting: a novel approach to reach bone using zoledronate anchored nanoparticles
Vinoth Khandelwal 1,2,3 Kiran Chaudhari 3,4 Abhinesh Kumar 4 Anil Mishra 5 Jukka Monkkonen 3 Rayasa RamachandraMurthy 4
2Consorzio Mario Negri Sud, Santa Maria Imbaro, Italy
3University of Eastern Finland, Kuopio, Finland
4The Maharaja Sayajirao University of Baroda, Vadodara, India
5Institute of Nuclear Medicine and Allied Sciences, Delhi, India
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<0.01), 20 (p<0.001) and 155 (p<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.
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