Synthesis and in vitro assessment of novel water-soluble dextran- docetaxel conjugates as potential pH sensitive system for tumor- targeted delivery Elahehnaz Parhizkar, 1 Saeid Daneshamouz, 1 Soliman Mohammadi-Samani, 1,2 Amirhossein Sakhteman, 3 Golnaz Parhizkar, 4 Mahmoud Omidi, 5 Fatemeh Ahmadi 1,2 1 Department of Pharmaceutics, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz 71468-64685, Iran 2 Research Center for Nanotechnology in Drug Delivery, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz 71468-64685, Iran 3 Department of Medicinal Chemistry, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz 71468-64685, Iran 4 Department of Chemistry, University of Isfahan, Isfahan 81746-73441, Iran 5 Department of Pharmacology and Toxicology, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz 71468-64685, Iran Correspondence to: F. Ahmadi (E - mail: ahmadi_f@sums.ac.ir) ABSTRACT: Docetaxel is a potent taxane agent mostly used in breast, lung, and prostate cancers. Its low water solubility is the major drawback that leads to use of Tween 80 as surfactant and ethanol as solvent in market formulation. But, these excipients cause severe hypersensitivity reactions. In this study, docetaxel was conjugated to biocompatible polymer, dextran 70 kDa, via a pH sensitive linker to enhance solubility and diminish the need of surfactants. Folic acid was also conjugated to dextran to provide targeted delivery. Synthesized conjugates were examined for solubility, hemo-compatibility, stability, and cytotoxicity on MCF-7 and MDA-MB-231 cell lines. Results showed about 1200-fold enhancement in water solubility by dextran and 280-fold by dextran-folate conjugation. Conju- gates released the drug in a pH-dependent manner and faster hydrolysis was observed in pH 5.4 than physiological pH 7.4. Docetaxel-dextran conjugates showed proper hemo-compatibility and presented greater cytotoxicity than docetaxel solution. Higher cytotoxicity was seen in folate conjugated samples and the final conjugates targeted by folate would be suitable novel substitutions for currently marketed formulation. V C 2017 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2017, 134, 45457. KEYWORDS: cell toxicity; dextran; docetaxel; folate conjugate; hemo-compatibility; water solubility Received 10 January 2017; accepted 20 June 2017 DOI: 10.1002/app.45457 INTRODUCTION Docetaxel (DTX) is a potent taxane derivative used in many types of cancer especially breast cancer, nonsmall cell lung cancer, and prostate cancer. It is a semisynthetic analog of paclitaxel and has hydrophobic feature. Low water solubility is the major drawback of taxane drugs, which prompted researchers to find a suitable solvent for use in parenteral formulations. This effort finally led to use of Tween 80 as nonionic surfactant and ethanol as solvent for current market formulation of DTX. 1 Unfortunately, these excipients cause life-threatening hypersensitivity reactions that should be managed by premedication regimes. 2 Main goal of recent studies on DTX is not only to increase DTX water solubility, but also to diminish the use of Tween 80 and ethanol by designing novel drug delivery sys- tems such as solid self-emulsifying systems, 3 polymeric micelles, 4 nanoparticles, nano drug conjugates, 2 and liposomes. 5 The rationale of all mentioned approaches is enhancement in DTX tumor targeting by enhanced permeability and retention (EPR) effect of nanocarriers in addition to reduction of side effects. 6,7 It is crucial that if the solubility problems of DTX are overcome, the main obstacle in drug formulation will be resolved. One of the promising approaches for solubility improvement is to prepare drug-polymer nano conjugates—known as pro- drugs—in which the drug is conjugated covalently to the poly- mer backbone to improve the solubility, bioavailability, efficacy, and pharmacokinetics parameters of the conjugated drug. 8,9 Most recently marketed nano conjugates of taxane derivatives is Xyotax (also known as Opaxio) which contains paclitaxel polyglutamate conjugate. The most challenging feature of prodrugs preparation is to select the polymer with proper pharmaceutical characteristics 9 V C 2017 Wiley Periodicals, Inc. WWW.MATERIALSVIEWS.COM J. APPL. POLYM. SCI. 2017, DOI: 10.1002/APP.45457 45457 (1 of 7)