Colloids and Surfaces B: Biointerfaces 146 (2016) 152–160 Contents lists available at ScienceDirect Colloids and Surfaces B: Biointerfaces journal homepage: www.elsevier.com/locate/colsurfb Cationic drug-based self-assembled polyelectrolyte complex micelles: Physicochemical, pharmacokinetic, and anticancer activity analysis Thiruganesh Ramasamy a , Bijay Kumar Poudel a , Himabindu Ruttala a , Ju Yeon Choi a , Truong Duy Hieu a , Kandasamy Umadevi b , Yu Seok Youn c , Han-Gon Choi d , Chul Soon Yong a,∗ , Jong Oh Kim a,∗ a College of Pharmacy, Yeungnam University, 214-1 Dae-dong, Gyeongsan 712-749, South Korea b St. Paul’s College of Pharmacy, Osmania University, Hyderabad, Telangana, India c School of Pharmacy, SungKyunKwan University, 300 Cheoncheon-dong, Jangan-gu, Suwon, 440-746, South Korea d College of Pharmacy, Institute of Pharmaceutical Science and Technology, Hanyang University, 55, Hanyangdaehak-ro, Sangnok-gu, Ansan 426-791, South Korea a r t i c l e i n f o Article history: Received 22 March 2016 Received in revised form 31 May 2016 Accepted 2 June 2016 Available online 5 June 2016 Keywords: Nanofabrication Polyelectrolyte complex micelles Cationic drugs Pharmacokinetic Anticancer activity a b s t r a c t Nanofabrication of polymeric micelles through self-assembly of an ionic block copolymer and oppositely charged small molecules has recently emerged as a promising method of formulating delivery systems. The present study therefore aimed to investigate the interaction of cationic drugs doxorubicin (DOX) and mitoxantrone (MTX) with the anionic block polymer poly(ethylene oxide)-block-poly(acrylic acid) (PEO-b-PAA) and to study the influence of these interactions on the pharmacokinetic stability and anti- tumor potential of the formulated micelles in clinically relevant animal models. To this end, individual DOX and MTX-loaded polyelectrolyte complex micelles (PCM) were prepared, and their physicochemical properties and pH-responsive release profiles were studied. MTX-PCM and DOX-PCM exhibited a differ- ent release profile under all pH conditions tested. MTX-PCM exhibited a monophasic release profile with no initial burst, while DOX-PCM exhibited a biphasic release. DOX-PCM showed a higher cellular uptake than that shown by MTX-PCM in A-549 cancer cells. Furthermore, DOX-PCM induced higher apoptosis of cancer cells than that induced by MTX-PCM. Importantly, both MTX-PCM and DOX-PCM showed pro- longed blood circulation. MTX-PCM improved the AUC all of MTX 4-fold compared to a 3-fold increase by DOX-PCM for DOX. While a definite difference in blood circulation was observed between MTX-PCM and DOX-PCM in the pharmacokinetic study, both MTX-PCM and DOX-PCM suppressed tumor growth to the same level as the respective free drugs, indicating the potential of PEGylated polymeric micelles as effective delivery systems. Taken together, our results show that the nature of interactions of cationic drugs with the polyionic copolymer can have a tremendous influence on the biological performance of a delivery system. © 2016 Elsevier B.V. All rights reserved. 1. Introduction Conventional chemotherapeutic approach is the main treat- ment option for cancer [1]. Despite great strides made in understanding cancer biology, conventional chemotherapeutic drugs are characterized by non-specific distribution and high accu- mulation in healthy cells, leading to dose-limiting side effects that seriously impede their clinical application [2]. To minimize side effects and improve therapeutic efficacy of chemotherapeu- ∗ Corresponding authors. E-mail addresses: csyong@ynu.ac.kr (C.S. Yong), jongohkim@yu.ac.kr (J.O. Kim). tic drugs, various drug delivery systems have been developed. Among them, block copolymer-based self-assembled polymeric micelles have demonstrated promising potential in the delivery of anticancer drugs. The nanosized micelles offer many advan- tages, including uniform size distribution, core-shell architecture, high drug loading, and physical stability [3,4]. Polyethylene glycol (PEG) is widely used to graft the hydrophobic part of amphiphilic polymers and form the outer shell of the micelles. Such polymeric micelles have been shown to increase the systemic circulation time of drugs and preferentially accumulate in tumors via enhanced permeability and retention (EPR) effect [5]. Polyelectrolyte complex micelles (PCM), a special class of micelles formed by electrostatic interaction of opposite charged http://dx.doi.org/10.1016/j.colsurfb.2016.06.004 0927-7765/© 2016 Elsevier B.V. All rights reserved.