Preparation and in vitro evaluation of actively targetable nanoparticles for SN-38 delivery against HT-29 cell lines Pedram Ebrahimnejad, PharmD a,b , Rassoul Dinarvand, PharmD, PhD a,c, ⁎ , Abolghasem Sajadi, PharmD, PhD d , Mahmoud Reza Jaafari, PharmD, PhD b , Ali Reza Nomani, PharmD a,e , Ebrahim Azizi, PharmD, PhD c,e , Mazda Rad-Malekshahi, PharmD a , Fatemeh Atyabi, PharmD, PhD a,c a Novel Drug Delivery Systems Lab, Department of Pharmaceutics, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran b Biotechnology Research Centre, Faculty of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran c Medical Nanotechnology Research Centre, Tehran University of Medical Sciences, Tehran, Iran d Pharmacological Research Centre of Medicinal Plants, Faculty of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran e Pharmacology Research Lab, Department of Toxicology-Pharmacology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran Received 20 February 2009; accepted 2 October 2009 Abstract SN-38 (7-ethyl-10-hydroxycamptothecin) is the active metabolite of irinotecan, which is 100-to 1000-fold more cytotoxic than irinotecan. Nevertheless, extreme hydrophobicity of SN-38 has prevented its clinical use. One way of improving the solubility and stability of SN-38 is to formulate the drug into nanoparticles. Folic acid has been widely used as a targeting moiety for various anticancer drugs. For folate- receptor–targeted anticancer therapy, SN-38 nanoparticles were produced using poly-lactide-co-glycolide–polyethylene glycol–folate (PLGA-PEG-FOL) conjugate by emulsification/solvent evaporation method. The FOL-conjugated di-block copolymer was synthesized by coupling the PLGA-PEG-NH 2 di-block copolymer with an activated folic acid. The conjugates were used for the formation of SN-38 nanoparticles with an average size of 200 nm in diameter. The SN-38 targeted nanoparticles showed a greater cytotoxicity against HT-29 cancer cells than SN-38 nontargeted nanoparticles. These results suggested that folate-targeted nanoparticles could be a potentially useful delivery system for SN-38 as an anticancer agent. From the Clinical Editor: SN-38 is the active metabolite of the chemotherapy agent irinotecan, which is 100-1000 fold more cytotoxic than irinotecan, but its extreme hydrophobicity has prevented its clinical use. In this paper, the authors present a nanotechnology-based approach targeting the folate-receptor with SN-38 loaded nanoparticles, demonstrating stronger cytotoxicity against HT-29 cancer cells than with control nanoparticles. © 2010 Elsevier Inc. All rights reserved. Key words: Folate targeting; Nanoparticles; Nanotechnology; PLGA; SN-38 Irinotecan is an anticancer agent of the camptothecin family. Irinotecan is activated by hydrolysis to SN-38 (7-ethyl-10- hydroxy-camptothecin), an inhibitor of topoisomerase I. 1 The inhibition of topoisomerase I by the active metabolite SN-38 eventually leads to inhibition of both DNA replication and transcription. Irinotecan is commercially available as Camptosar (Pfizer Inc, New York, New York). 2-4 The chemical structures of SN-38 and irinotecan are shown in Figure 1. It is reported that only a small proportion (2% to 8%) of irinotecan is converted to SN-38 in the liver and tumor cells; for this purpose a large dosage of irinotecan is needed to obtain therapeutic efficacy. 1,3 SN-38 is highly potent in vitro as an anticancer drug against many malignancies including colorectal, lung, lymphoma, gastric, cervical, and ovarian cancer. 1,4,5 SN-38 is a potent antitumor agent, approximately 1000-fold more active than irinotecan, but suffers from limited direct clinical applications because of poor aqueous solubility. 3,4,6 One way of improving the solubility and BASIC SCIENCE Nanomedicine: Nanotechnology, Biology, and Medicine 6 (2010) 478 – 485 Original Article www.nanomedjournal.com This work was supported by Medical Nanotechnology Research Center, Tehran University of Medical Sciences, and the Special Office for Nanotechnology Development. ⁎ Corresponding author: Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran PO Box 14155-6451, Iran. E-mail address: dinarvand@tums.ac.ir (R. Dinarvand). 1549-9634/$ – see front matter © 2010 Elsevier Inc. All rights reserved. doi:10.1016/j.nano.2009.10.003 Please cite this article as: P., Ebrahimnejad, et al, Preparation and in vitro evaluation of actively targetable nanoparticles for SN-38 delivery against HT-29 cell lines. Nanomedicine: NBM 2010;6:478-485, doi:10.1016/j.nano.2009.10.003