Folic acid-functionalized drug delivery platform of resveratrol based on Pluronic 127/D-α-tocopheryl polyethylene glycol 1000 succinate mixed micelles

International Journal of Nanomedicine, Mar 2017

Folic acid-functionalized drug delivery platform of resveratrol based on Pluronic 127/D-α-tocopheryl polyethylene glycol 1000 succinate mixed micelles Jifu Hao,* Tiantian Tong,* Kai Jin, Qiannan Zhuang, Te Han, Yanping Bi, Jianzhu Wang, Xiaodan Wang College of Pharmacy, Taishan Medical University, Taian, People’s Republic of China *These authors contributed equally to this work Abstract: A folic acid (FA)-functionalized drug vehicle platform based on Pluronic 127 (P127)/D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) mixed micelles was orchestrated for an effective delivery of the model drug resveratrol in order to address the problem of poor water solubility and rapid metabolism of resveratrol and improve its targeted accumulation at tumor site. The FA-decorated mixed micelles were prepared using thin-film hydration method and optimized by central composite design approach. The micelles were also characterized in terms of size and morphology, drug entrapment efficiency and in vitro release profile. In addition, the cytotoxicity and cell uptake of the micelles were evaluated in folate receptor-overexpressing MCF-7 cell line. In vivo pharmacokinetic and biodistribution studies were also performed. The average size of the micelles was ~20 nm with a spherical shape and high encapsulation efficiency (99.67%). The results of fluorescence microscopy confirmed the targeting capability of FA-conjugated micelles in MCF-7 cells. FA-modified micelles exhibited superior pharmacokinetics in comparison with that of solution. Further, the low accumulation of resveratrol-loaded FA micelles formulation in the heart and kidney avoided toxicity of these vital organs. It could be concluded that folate-modified P127/TPGS mixed micelles might serve as a potential delivery platform for resveratrol. Keywords: resveratrol, Pluronic 127/TPGS, mixed micelles, folic acid conjugation

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Folic acid-functionalized drug delivery platform of resveratrol based on Pluronic 127/D-α-tocopheryl polyethylene glycol 1000 succinate mixed micelles

Authors Hao J, Tong T, Jin K, Zhuang Q, Han T, Bi Y, Wang J, Wang X Received 13 December 2016 Accepted for publication 24 February 2017 Published 24 March 2017 Volume 2017:12 Pages 2279—2292 DOI https://doi.org/10.2147/IJN.S130094 Checked for plagiarism Yes Review by Single-blind Peer reviewers approved by Dr Jiang Yang Peer reviewer comments 2 Editor who approved publication: Dr Lei Yang Jifu Hao,* Tiantian Tong,* Kai Jin, Qiannan Zhuang, Te Han, Yanping Bi, Jianzhu Wang, Xiaodan Wang College of Pharmacy, Taishan Medical University, Taian, People’s Republic of China *These authors contributed equally to this work Abstract: A folic acid (FA)-functionalized drug vehicle platform based on Pluronic 127 (P127)/D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) mixed micelles was orchestrated for an effective delivery of the model drug resveratrol in order to address the problem of poor water solubility and rapid metabolism of resveratrol and improve its targeted accumulation at tumor site. The FA-decorated mixed micelles were prepared using thin-film hydration method and optimized by central composite design approach. The micelles were also characterized in terms of size and morphology, drug entrapment efficiency and in vitro release profile. In addition, the cytotoxicity and cell uptake of the micelles were evaluated in folate receptor-overexpressing MCF-7 cell line. In vivo pharmacokinetic and biodistribution studies were also performed. The average size of the micelles was ~20 nm with a spherical shape and high encapsulation efficiency (99.67%). The results of fluorescence microscopy confirmed the targeting capability of FA-conjugated micelles in MCF-7 cells. FA-modified micelles exhibited superior pharmacokinetics in comparison with that of solution. Further, the low accumulation of resveratrol-loaded FA micelles formulation in the heart and kidney avoided toxicity of these vital organs. It could be concluded that folate-modified P127/TPGS mixed micelles might serve as a potential delivery platform for resveratrol. Keywords: resveratrol, Pluronic 127/TPGS, mixed micelles, folic acid conjugation Introduction In recent years, resveratrol, a naturally occurring polyphenol and phytoalexin, abundant in berry, grape, peanut and other plants, has sparked significant focus due to its beneficial effects on human health, which include antioxidant, anti-inflammatory, cardioprotective and antitumor activities.1 Some literature have illustrated that resveratrol can both inhibit tumor cell growth and promote cell apoptosis exerting its antitumor effect by means of some related cell signaling pathways.2,3 However, poor bioavailability of resveratrol owing to factors such as low aqueous solubility, easy photodegradation and extensive first-pass metabolism hinders its further clinical application.4 Therefore, the primary problem is how to design effective and suitable drug delivery systems (DDSs) for resveratrol to address the aforementioned shortcomings. Innovative DDSs of resveratrol, such as polymeric nanoparticles, cyclodextrins, colloidal mesoporous silica nanoparticles and liposomes, have been fabricated to enhance aqueous solubility and bioavailability, improve physicochemical stability and achieve targeted or controlled drug release.5–7 Recently, different classical and successful nanotherapeutics used to transport anticancer drugs into tumors have been fabricated and applied in order to improve the anticancer effect of chemotherapeutic drugs, the most prominent among which include polymeric nanocarriers such as liposomes, supramolecular derivatives and ultradeformable vesicles.8–10 As one of the promising nanoparticular approaches, the mixed micelle carriers formed by triblock copolymers for delivery of anticancer drugs have been basically exploited in various clinical applications for the merits of smaller size, self-assembling ability, solubilization and protection against unstable drugs.11 Nonetheless, many anticancer drugs incorporated into micelles show rare selectivity and limited orientation for malignant tumors because of their passive targeting efficiency described by the well-known enhanced permeability and retention (EPR) effect. These passive DDSs have exhibited distinctly nonspecific distribution in systemic administration and resulted in toxicity against normal tissues. Selective and preferred DDSs intended to specific sites will not only improve therapeutic efficacy but also avoid negative side effects on normal cells and tissues.12 Accordingly, it is necessary to make use of the specific receptors present on the surface of cell membrane to achieve better tumor targeting. Some strategies of conjugation of targeting ligand molecules, such as folic acid (FA), mannose, RGD peptide and transferrin, to block polymers for selective delivery, have been reported in published literature.13 The folic acid receptor (FAR) h (...truncated)


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Jifu Hao, Tiantian Tong, Kai Jin, Qiannan Zhuang, Te Han, Yanping Bi, Jianzhu Wang, Xiaodan Wang. Folic acid-functionalized drug delivery platform of resveratrol based on Pluronic 127/D-α-tocopheryl polyethylene glycol 1000 succinate mixed micelles, International Journal of Nanomedicine, 2017, pp. 2279-2292, DOI: 10.2147/IJN.S130094