Reversibly stabilized multifunctional dextran nanoparticles efficiently deliver doxorubicin into the nuclei of cancer cells.

Drug delivery has been considered as the key to the clinical success of numerous drugs. In the past decade, with an aim to improve chemotherapy, tremendous effort has been directed to the development of polymer nanoparticles for the controlled delivery of anticancer drugs, including doxorubicin (DOX) and paclitaxel (PTX). These nanovehicles offer several unique features, such as enhancing the aqueous solubility and bioavailability of the drug, prolonging the circulation time, preferential accumulation at the tumor sites by the enhanced permeability and retention (EPR) effect, and reducing systemic side effects. 14] However, one practical challenge with nanoparticles is their low stability in vivo because of the large dilution volume and/or interactions with cells and biomolecules present in the blood, which often lead to premature drug release, aggregation, and a diminished ability of the drug to reach its target. In the past few years, different cross-linking approaches have been adopted to improve their stability, for example, through cross-linking of the hydrophilic shell, within the hydrophobic core, or at the core–shell interface. It should be noted, on the other hand, that overly stable nanoparticles are also far from optimal for drug-delivery applications, because drug efficacy is significantly reduced by the prohibited release of drugs from the nanoparticles even though they reach the target sites. 24] Last but not least, few of the cross-linked nanoparticles so far reported are biocompatible and degradable, 20] which are nevertheless fundamental prerequisites for biomedical applications. There exists a large difference in the redox potential between the mildly oxidizing extracellular milieu and the reducing intracellular fluids, such as the cytoplasm and the cell nucleus, which renders reduction-sensitive polymers particularly appealing for biomedical applications. For example, reduction-sensitive polymer/DNA complexes, polyion complex micelles, 29] micelles, polymersomes, cross-linked polymersomes, and degradable nanogels have been reported to achieve fast intracellular release of DNA, siRNA, or drugs. Herein, we report on reversibly stabilized multifunctional dextran nanoparticles for the triggered intracellular delivery of DOX, one of the most potent lipophilic anticancer drugs widely used in the clinics. The nanoparticles were prepared from dextran-lipoic acid derivatives (Dex-LAs) and were readily cross-linked using a catalytic amount of dithiothreitol (DTT; Figure 1). Dextran is a natural analogue of polyethylene glycol (PEG), and has been used in a range of biomedical applications because of its excellent aqueous solubility, biocompatibility, and nonfouling properties. Lipoic acid is produced naturally in the human body and commonly used as an antioxidant drug for treating diseases such as diabetes and HIV. 40] Thus, these nanoparticles are based solely on well-accepted medical materials. The resulting cross-linked dextran nanoparticles (C-DNPs) are stable against dilution and a high salt concentration. Notably, they showed a high drug loading efficiency of 84 %. The in vitro release studies showed that the release of DOX was minimal (ca. 10%) even under extensive dilution, while in the presence of 10 mm DTT (which mimics the intracellular reductive environment) over 90 % of the DOX was released in 11 h. Confocal laser scanning microscopy (CLSM) studies using HeLa and RAW 264.7 (a mouse leukaemic monocyte macrophage cell line) cells showed a rapid and efficient delivery of DOX into the cell nucleus (Figure 1). MTT assays showed that DOX-loaded C-DNP had a similar drug efficacy as the non-cross-linked counterparts. These dextran nanoparticles, although extremely simple, display multifunctionalities including degradability, biocompatibility, and reversible cross-linking properties, which renders them superb for the tumor-targeted delivery of anticancer drugs. The Dex-LA conjugates were conveniently prepared by treating dextran with lipoic acid anhydride in DMSO (see Scheme S1 in the Supporting Information). H NMR spectroscopic analysis showed that the lipoic acid was successfully grafted on to the dextran (see Figure S1 in the Supporting Information). The degree of substitution (DS, defined as the number of LA units per 100 anhydroglucosidic (AHG) units), as determined by comparing the signals at d = 1.86–1.91 ppm [*] Y. -L. Li, Z. Liu, Dr. R. Cheng, Prof. Dr. F. Meng, Prof. Dr. S. -J. Ji, Prof. Dr. Z. Zhong Biomedical Polymers Laboratory, and Key Laboratory of Organic Synthesis of Jiangsu Province College of Chemistry Chemical Engineering and Materials Science Soochow University, Suzhou, 215123 (P.R. China) Fax: (+ 86)512-6588-0098 E-mail: fhmeng@suda.edu.cn zyzhong@suda.edu.cn Homepage: http://chemistry.suda.edu.cn/lab/swyygfz