Lipoyl Ester Terminated Star PLGA as a Simple and Smart Material for Controlled Drug Delivery Application Xiuxiu Wang, † Ru Cheng,* ,† Liang Cheng, †,‡ and Zhiyuan Zhong* ,† † Biomedical Polymers Laboratory, and Jiangsu Key Laboratory of Advanced Functional Polymer Design and Application, College of Chemistry, Chemical Engineering and Materials Science, Soochow University, Suzhou 215123, People’s Republic of China ‡ Department of Pharmaceutics, College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, People’s Republic of China * S Supporting Information ABSTRACT: PLGA, a copolymer of lactide and glycolide, is one of the most used biodegradable polymers that find a wide range of biomedical applications including drug delivery and tissue engineering. However, in spite of remarkable advancement, nanotherapeutics based on PLGA might have drawbacks of inadequate stability, drug leakage, and slow drug release at the tumor site, which reduces its targeting ability and therapeutic efficacy. Here, we report that direct modification of star PLGA ends with lipoic acid, a natural antioxidant present in our human body, affords a smart material (sPLGA-LA) that forms reversibly crosslinked and bioresponsive multifunctional nanoparticles (sPLGA XNPs). Interestingly, sPLGA XNPs obtained in the presence of 23.0 wt % PEG-PDLLA displayed a small hydrodynamic size of 73 ± 1.2 nm, high stability against dilution and 10% serum, while fast destabilization under a reductive environment. Moreover, sPLGA XNPs achieved efficient loading of lipophilic anticancer drug model, doxorubicin (DOX), at a theoretical drug loading content of 13.3 wt %, giving DOX-loaded sPLGA XNPs with reduced drug leakage under physiological conditions as well as significantly accelerated drug release under 10 mM glutathione condition compared with both linear and star PLGA controls (denoted as lPLGA NPs and sPLGA NPs, respectively). Confocal microscopy and flow cytometry displayed obviously stronger DOX fluorescence in B16F10 melanoma cells treated with DOX-loaded sPLGA XNPs than with lPLGA and sPLGA counterparts. MTT assays revealed that DOX-sPLGA XNPs caused 2.4- and 4.2-fold higher antitumor activity toward B16F10 cells than DOX-sPLGA NPs and DOX-lPLGA NPs, respectively. Notably, in vivo pharmacokinetics studies showed prolonged circulation time and significantly improved AUC for DOX-sPLGA XNPs over lPLGA NPs control. Hence, lipoyl ester terminated star PLGA emerges as a simple and smart material for better-controlled anticancer drug delivery. 1. INTRODUCTION PLGA, a copolymer of lactide and glycolide, is one of the most used biodegradable polymers that find a wide range of biomedical applications including drug delivery and tissue engineering. 1-4 Several clinical drug formulations like Lupron Depot, Decapeptyl, and Nutropin Depot used to treat prostate cancer, lung cancer, and growth hormone deficiency are based on PLGA microparticles. 5,6 Notably, BIND-014, a first active targeting docetaxel nanomedicine tested in human patients, is also fabricated from PLGA. 7,8 The wide use of PLGA is because of its superior biocompatibility, in vivo biodegradability, and approval by the U.S. FDA for use in medical devices. 9-12 It should be noted, however, that nanotherapeutics based on PLGA expose several drawbacks such as inadequate stability, drug leakage, and slow and fractional drug release at the tumor site, which significantly reduce its targeting ability and therapeutic efficacy. 13-15 To this end, different strategies were employed to produce functional PLGA nanoparticles. For example, to increase their stability in vivo, PLGA nanoparticles were coated with natural substances such as blood cell membrane 16,17 and hyaluronic acid. 18-20 To enhance cytoplas- mic drug release, stimuli-responsive PLGA nanoparticles were designed by incorporating pH-sensitive polymers like poly(L- histidine), poly(β-amino ester), and 2-aminoethyl methacryla- mide containing brush-like copolymers or using reduction- sensitive polymers like PEG-SS-hexadecyl or vitamin E-SS- oligo(methyl diglycol L-glutamate) as a surfactant. 21-27 The use of sophisticated chemistry or exotic materials, however, makes these functional PLGA nanoparticles less interesting for clinical translation. We report here that direct modification of star PLGA ends with lipoic acid, a natural antioxidant present in our human body, 28,29 affords a novel and smart material (sPLGA-LA) that forms reversibly crosslinked and bioresponsive multifunctional nanoparticles (sPLGA XNPs; Figure 1). The synthesis of sPLGA-LA and sPLGA XNPs, stability and reduction-triggered doxorubicin (DOX) release, as well as in vitro antitumor performance and in vivo pharmacokinetics of DOX-loaded sPLGA XNPs were investigated and compared with both linear and star PLGA controls (denoted as lPLGA NPs and sPLGA NPs, respectively). 2. RESULTS AND DISCUSSION 2.1. Preparation of Lipoyl Ester Terminated Star PLGA (sPLGA-LA) and sPLGA XNPs. sPLGA-LA was easily synthesized through esterification of five-armed sPLGA (M n = 15 kg/mol) with lipoic acid anhydride (LAA; SI, Figure 1). 1 H NMR analysis showed, besides signals attributed to sPLGA Received: January 26, 2018 Revised: March 15, 2018 Published: March 19, 2018 Note pubs.acs.org/Biomac Cite This: Biomacromolecules 2018, 19, 1368-1373 © 2018 American Chemical Society 1368 DOI: 10.1021/acs.biomac.8b00130 Biomacromolecules 2018, 19, 1368-1373