Paclitaxel loaded PEGylated gleceryl monooleate based nanoparticulate carriers in chemotherapy Vikas Jain a , Nitin K. Swarnakar a , Prabhat R. Mishra b , Ashwni Verma b , Ankur Kaul c , Anil K. Mishra c , Narendra K. Jain a, * a Pharmaceutics Research Laboratory, Department of Pharmaceutical Sciences, Dr. H. S. Gour University, Sagar 470003, M.P., India b Pharmaceutics Division, Central Drug Research Institute, Chattar Manzil Palace, Lucknow 226001, U.P., 226001, India c Division of Cyclotron & Radiopharmaceutical Sciences, Institute of Nuclear Medicine and Allied Sciences (INMAS), DRDO, Delhi, 110054, India article info Article history: Received 6 June 2012 Accepted 22 June 2012 Available online 17 July 2012 Keywords: Paclitaxel PEGylation Liquid crystalline nanoparticles Pharmacoscintigraphy SAXS Anticancer efficacy abstract A PEGylated drug delivery system of paclitaxel (PTX), based on glyceryl monooleate (GMO) was prepared by optimizing various parameters to explore its potential in anticancer therapy. The prepared system was characterized through polarized light microscopy, TEM, AFM and SAXS to reveal its liquid crystalline nature. As GMO based LCNPs exhibit high hemolytic toxicity and faster release of entrapped drug (66.2  2.5% in 24 h), PEGylation strategy was utilized to increase the hemocompatibility (reduction in hemolysis from 60.3  10.2 to 4.4  1.3%) and control the release of PTX (43.6  3.2% released in 24 h). The cytotoxic potential and cellular uptake was assessed in MCF-7 cell lines. Further, biodistribution studies were carried out in EAT (Ehrlich Ascites tumor) bearing mice using 99m Tc-(Technetium radio- nuclide) labeled formulations and an enhanced circulation time and tumor accumulation (14 and 8 times, respectively) were observed with PEGylated carriers over plain ones, at 24 h. Finally, tumor growth inhibition experiment was performed and after 15 days, control group exhibited 15 times enhancement in tumor volume, while plain and PEGylated systems exhibited only 8 and 4 times enhancement, respectively, as compared to initial tumor volume. The results suggest that PEGylation enhances the hemocompatibility and efficacy of GMO based system that may serve as an efficient i.v. delivery vehicle for paclitaxel. Ó 2012 Elsevier Ltd. All rights reserved. 1. Introduction Paclitaxel (PTX), a taxane obtained from Pacific yew, is a micro- tubule stabilizer, used in number of malignancies [1]. It is highly lipophilic in nature (log P ¼ 3.20; solubility in water <1.0 mg/mL) [2] and its injectable form is available in a vehicle comprising of Cre- mophor EL and ethanol (1:1 v/v) [3]. The extensive use of this form is limited in oncology owing to undesired reactions like neuro- toxicity, anaphylaxis, altered pharmacokinetics and nephrotoxicity. Furthermore, precipitation associated with aqueous dilution always poses a major concern [4]. Although, various approaches were employed to enhance the aqueous solubility of PTX and to achieve controlled release behavior by utilizing emulsions [5], liposomes [6], micelles [7], nanoparticles [8] and other novel approaches [9,10], yet each suffers from known limitations. Development of a safe and efficacious dosage form for the PTX delivery remains a challenging task for scientists, till date. Thus, there is a need for developing a formulation capable of bypassing the solubility and toxicity limitation of PTX. In this context, glyceryl monooleate (GMO) based liquid crystalline nanoparticles (LCNPs) have been tried as an alternate approach. LCNPs offer various outstanding advantages like self-assembly, flexible structure, surface free groups for functionalization, solu- bility enhancing properties and capability to incorporate variety of drugs. The presence of liquid crystalline phases (gel form) in self assembled amphiphilic molecules has been established by Luzzati and Hasson [11], who demonstrated self-assembling properties of lipids into different non-lamellar (sponge, bicontinuous cubic, reversed hexagonal, and reversed micellar cubic) phases. However, their high viscosity and tackiness render them of limited utility in drug delivery. Later on, analogous to liposomes, non-lamellar phases were dispersed using surfactants/polymeric stabilizers and their dispersion were termed as cubosomes (aqueous dispersions of a cubic phase) and hexosomes (aqueous dispersions of a reverse hexagonal phase) [12e14]. These liquid crystalline materials (phases and nanoparticulate dispersion) received much attention * Corresponding author. Tel.: þ91 7582 264712; fax: þ91 7582 236613. E-mail addresses: jnarendr@yahoo.co.in, jainvk@hotmail.com (N.K. Jain). Contents lists available at SciVerse ScienceDirect Biomaterials journal homepage: www.elsevier.com/locate/biomaterials 0142-9612/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.biomaterials.2012.06.056 Biomaterials 33 (2012) 7206e7220