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Is an Alternative Drug Delivery System Needed for Docetaxel? The Role of Controlling Epimerization in Formulations and Beyond

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ABSTRACT

Purpose

The presence of 7-epidocetaxel in docetaxel injection and in vivo epimerisation has been reported to be the cause for development of tumor resistance to chemotherapy including docetaxel by inducing tumor cell protein cytochrome P450 1B1. The objective of this study was to determine systemic toxicity of Taxotere® containing 10% 7-epidocetaxel and to develop PEGylated liposomal injection that could resist epimerization in vivo. Another need for PEGylated liposomal delivery of docetaxel is to avoid reported hypersensitivity reactions of marketed products like Taxotere® and Duopafei® containing high concentration of tween-80.

Methods

The PEGylated liposomes loaded with docetaxel were prepared using thin film hydration method. The in vivo toxicity of Taxotere® containing 10% 7-epimer was studied in B16F10 experimental metastasis model.

Results

B16F10 experimental metastasis model using C57BL/6 mice injected with Taxotere® containing 10% 7-epimer showed higher weight loss as compared to Taxotere® containing no epimer at single dose of 40 mg/kg indicating higher systemic toxicity. Incubation of PEGylated liposomes with phosphate buffer saline (pH 7.4) containing 0.1% w/v Tween-80 for 48 h showed better resistance to docetaxel degradation when compared with Taxotere® injection indicating better in vivo stability of liposomal docetaxel. In addition, PEGylated liposomes showed enhanced in vitro cytotoxicity, against A549 and B16F10 cells, than Taxotere®.

Conclusion

We can therefore expect less in vivo conversion of liposomal loaded docetaxel into 7-epimer, more passive targeting to tumor tissues, decreased 7-epimer induced systemic toxicity and tumor resistance to chemotherapy compared to Taxotere®. Further in vivo studies are needed to ascertain these facts.

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ACKNOWLEDGMENTS AND DISCLOSURES

The authors would like to thank All India Council for Technical Education (AICTE), India, for grant support (F.N.:1-10/RID/NDF-PG(22)/2009-10). Peeyush N. Goel is supported by CSIR-SRF, India. The authors thank Lipoid GMBH (Ludwigshafen, Germany) for providing phospholipids (HSPC, DPPC, DSPE-mPEG2000 and DPPG) as gift samples. Authors also thank Fresenius Kabi Oncology Limited (Gurgaon, India) for providing docetaxel, 7-epidocetaxel and 10-oxo-7-epidocetaxel as gift samples. The authors would also like to thank the Flow Cytometry and Animal house facility during the course of the study.

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Authors and Affiliations

  1. TIFAC Centre of Relevance & Excellence in New Drug Delivery Systems, G.H. Patel Pharmacy Building, Pharmacy Department, The Maharaja Sayajirao University of Baroda, Donor’s Plaza Fatehgunj, Vadodara, 390002, Gujarat, India

    Arehalli S. Manjappa, Makam P. Vekataraju, Kinjal Makwana, Mukesh Ukawala & Rayasa S. Ramachandra Murthy

  2. Department of Pharmaceutics, Tatyasaheb Kore College of Pharmacy, Warananagar, Kolhapur District, Maharashtra, India

    Arehalli S. Manjappa

  3. Advanced Centre for Treatment Research & Education in Cancer, Tata Memorial Centre, Kharghar, Navi Mumbai, 410210, India

    Peeyush N. Goel, Yuvraj Nikam & Rajiv P. Gude

  4. Parul Institute of Pharmacy, P O Limda, Vadodara, Gujarat, India

    Kesarla S. Rajesh

  5. ISF College of Pharmacy, Firozpur, G. T. Road, Moga, 142001, Punjab, India

    Rayasa S. Ramachandra Murthy

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  1. Arehalli S. Manjappa
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  2. Peeyush N. Goel
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  4. Kesarla S. Rajesh
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  9. Rayasa S. Ramachandra Murthy
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Corresponding authors

Correspondence to Rajiv P. Gude or Rayasa S. Ramachandra Murthy.

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Manjappa, A.S., Goel, P.N., Vekataraju, M.P. et al. Is an Alternative Drug Delivery System Needed for Docetaxel? The Role of Controlling Epimerization in Formulations and Beyond. Pharm Res 30, 2675–2693 (2013). https://doi.org/10.1007/s11095-013-1093-5

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  • DOI: https://doi.org/10.1007/s11095-013-1093-5

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