Research Article Folate-Functionalized Thiomeric Nanoparticles for Enhanced Docetaxel Cytotoxicity and Improved Oral Bioavailability Muhammad Sajjad, 1 Muhammad Imran Khan, 1 Sara Naveed, 1 Sana Ijaz, 1 Omer Salman Qureshi, 2 Syed Atif Raza, 3 Gul Shahnaz, 4 and Muhammad Farhan Sohail 1,4,5,6 Received 22 October 2018; accepted 28 December 2018 Abstract. To achieve remotely directed delivery of anticancer drugs, surface-decorated nanoparticles with ligands are reported. In this study, folic acid– and thiol-decorated chitosan nanoparticles loaded with docetaxel (DTX-NPs) were prepared for enhanced cellular internalization in cancer cells and improved oral absorption. The DTX-NPs were explored through in vitro and in vivo parameters for various parameters. The DTX-NPs were found to be monodisperse nanoparticles with an average particle size of 158.50 ± 0.36 nm, a polydispersity index of 0.36 ± 0.0, a zeta potential of + 18.30 ± 2.52 mV, and an encapsulation efficiency of 71.47 ± 5.62%. The drug release from DTX-NPs followed the Korsmeyer-Peppas model with about 78% of drug release in 12 h. In in vitro cytotoxicity studies against folate receptor, positive MDA-MBB-231 cancerous cells showed improved cytotoxicity with IC 50 of 0.58 μg/mL, which is significantly lower as compared to docetaxel (DTX). Ex vivo permeation enhancement showed an efflux ratio of 0.99 indicating successful transport across the intestine. Oral bioavailability was significantly improved as C max and AUC were higher than DTX suspension. Overall, the results suggest that DTX-NPs can be explored as a promising carrier for oral drug delivery. KEY WORDS: docetaxel; nanoparticles; thiolated chitosan; folic acid; oral bioavailability. INTRODUCTION Docetaxel (DTX), an anticancer drug, belongs to the second-generation semisynthetic toxoids clinically used to treat advanced or metastatic breast cancer, gastric cancer, and lung cancer (1,2). DTX interferes with the microtubular network in cells by inhibiting of cell replication and depoly- merization, leading to cell seizure during growth cycle at late G 2 -M phase and, finally, cell death (3,4). The indications for DTX have been extended recently, to such an extent that in any comprehensive breast cancer chemo cycle, docetaxel is likely to be administered each day of the week and also regularly used in prostate and lung cancers. The oral formulations of DTX are still limited due to its low oral bioavailability (< 5%) which is the result of its extreme lipophilicity and practically insoluble property (4.93 μg/mL in water), hepatic first-pass metabolism, and its high affinity to P-glycoprotein efflux pump (5–7). The commercial formulation of DTX (Taxotere ® ) is manufactured by adding co-solvent and surfactants that induce some side effects including hypersensitivity, nephrotoxicity, and neurotoxicity (8,9). To overcome these formulation-related problems with drug solubility and permeability, nanotechnology has proven its potential through the development of liposomes, cyclodextrin conjugates, microspheres, polymeric micelles, polymer-drug conjugates, and various kinds of nanoparticles with defined attributes (10,11). Chitosan, a biodegradable, biocompatible, and cationic natural polysaccharide with low immunogenicity, has been considered as one of the most attractive materials for designing carrier for drugs, antibody, or small interfering RNA (siRNA) owing to its complex forming ability with negatively charged DNA; superior gene transfection, and more efficient protection against stress conditions (12–14). Folate receptors (FRs) are overexpressed in several malignant tumors cells like breast cancer and colon cancer, compared to the normal cells (15). At present, folic acid (FA) has emerged as a potential ligand for receptor-mediated tumor targeting and retains a high affinity for its receptor (16). Folic acid or its conjugates can be taken up by cells via endocytosis through the folate receptor, and at the 1 Riphah Institute of Pharmaceutical Sciences, Riphah International University, Lahore Campus, Lahore, Pakistan. 2 Faculty of Pharmacy, University of Lahore, Lahore, Pakistan. 3 College of Pharmacy, University of the Punjab, Lahore, Pakistan. 4 Department of Pharmacy, Faculty of Biological Sciences, Quaid-i- Azam University, Islamabad, 45320, Pakistan. 5 Department of Chemistry, SBA School of Science and Engineering (SBASSE), Lahore University of Management Sciences (LUMS), Lahore, 54792, Pakistan. 6 To whom correspondence should be addressed. (e–mail: farmacist.pk@gmail.com) AAPS PharmSciTech (2019) 20:81 DOI: 10.1208/s12249-019-1297-z 1530-9932/19/0000-0001/0 # 2019 American Association of Pharmaceutical Scientists