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Antiangiogenic Effect of Docetaxel and Everolimus as Individual and Dual-Drug-Loaded Micellar Nanocarriers

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ABSTRACT

Purpose

The in vitro inhibitory effect of Docetaxel (DTX) and Everolimus (EVR) alone and together in poly(ethylene glycol)-block-poly(D,L-lactic acid) (PEG-b-PLA) nanocarriers on angiogenic processes and acute toxicity in mice was evaluated.

Methods

PEG-b-PLA DTX and/or EVR nanocarriers were characterized for size, drug loading, stability, and drug release. Cell proliferation, tubule formation, and migration studies were performed in Human Umbilical Vein Endothelial Cells (HUVEC) and Maximum Tolerated Doses (MTD) studies were in mice.

Results

DTX and EVR loading was 1.93 and 2.00 mg/mL respectively with similar solubilities for dual-drug micelles. All micelles were below 30 nm with diffusion controlled drug release. The IC50 for DTX, EVR micelles were, 6.80 ± 0.67, 18.57 ± 2.86 and 0.65 ± 0.11 nM respectively with a synergistic inhibitory effect for dual-drug nanocarriers. Significant inhibition of tube formation occurred upon treatment with dual-drug nanocarriers as compared to individual micelles. EVR presence in dual-drug nanocarriers was able to significantly increase the inhibition of the migration of HUVEC by DTX. The MTDs for EVR, DTX and dual-drug micelles were 50, 30 and 20 mg/kg for each respectively.

Conclusions

DTX-EVR dual-drug nanocarriers have antiangiogenic effects in vitro mediated through cellular angiogenic process and possess clinically relevant MTD.

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ACKNOWLEDGMENTS AND DISCLOSURES

This study was supported by the grant from AACP New Pharmacy Faculty Research Award Program, Medical Research Foundation of Oregon New Investigator Grant and Oregon State University-Startup fund.

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Authors and Affiliations

  1. Department of Pharmaceutical Sciences, College of Pharmacy, Oregon State University, Corvallis, Oregon, USA

    Gyan P. Mishra, Bhuvana Shyam Doddapaneni, Duc Nguyen & Adam W. G. Alani

  2. Division of Pharmaceutical Sciences, College of Pharmacy, Oregon State University, Corvallis, Oregon, 97331, USA

    Adam W. G. Alani

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  1. Gyan P. Mishra
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  2. Bhuvana Shyam Doddapaneni
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  4. Adam W. G. Alani
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Correspondence to Adam W. G. Alani.

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Mishra, G.P., Doddapaneni, B.S., Nguyen, D. et al. Antiangiogenic Effect of Docetaxel and Everolimus as Individual and Dual-Drug-Loaded Micellar Nanocarriers. Pharm Res 31, 660–669 (2014). https://doi.org/10.1007/s11095-013-1188-z

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  • DOI: https://doi.org/10.1007/s11095-013-1188-z

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