Abstract
BackgroundReactive oxygen species (ROS)-responsive drug delivery systems (DDSs) are potential tools to minimize the side effects and substantially enhance the therapeutic efficacy of chemotherapy. However, it is challenging to achieve spatially and temporally controllable and accurate drug release in tumor sites based on ROS-responsive DDSs. To solve this problem, we designed a nanosystem combined photodynamic therapy (PDT) and ROS-responsive chemotherapy.MethodsIndocyanine green (ICG), an ROS trigger and photosensitizer, and pB-DOX, a ROS-responsive prodrug of doxorubicin (DOX), were coencapsulated in polyethylene glycol modified liposomes (Lipo/pB-DOX/ICG) to construct a combination therapy nanosystem. The safety of nanosystem was assessed on normal HEK-293 cells, and the cellular uptake, intracellular ROS production capacity, target cell toxicity, and combined treatment effect were estimated on human breast cancer cells MDA-MB-231. In vivo biodistribution, biosafety assessment, and combination therapy effects were investigated based on MDA-MB-231 subcutaneous tumor model.ResultsCompared with DOX·HCl, Lipo/pB-DOX/ICG showed higher safety on normal cells. The toxicity of target cells of Lipo/pB-DOX/ICG was much higher than that of DOX·HCl, Lipo/pB-DOX, and Lipo/ICG. After endocytosis by MDA-MB-231 cells, Lipo/pB-DOX/ICG produced a large amount of ROS for PDT by laser irradiation, and pB-DOX was converted to DOX by ROS for chemotherapy. The cell inhibition rate of combination therapy reached up to 93.5 %. After the tail vein injection (DOX equivalent of 3.0 mg/kg, ICG of 3.5 mg/kg) in mice bearing MDA-MB-231 tumors, Lipo/pB-DOX/ICG continuously accumulated at the tumor site and reached the peak at 24 h post injection. Under irradiation at this time point, the tumors in Lipo/pB-DOX/ICG group almost disappeared with 94.9 % tumor growth inhibition, while those in the control groups were only partially inhibited. Negligible cardiotoxicity and no treatment-induced side effects were observed.ConclusionsLipo/pB-DOX/ICG is a novel tool for on-demand drug release at tumor site and also a promising candidate for controllable and accurate combinatorial tumor therapy.
Highlights
Chemotherapy, as a mainstay in clinical cancer treatment, shows severe systemic toxicity resulting from the nonspecific drug distribution in the human body [1, 2]
Synthesis and characterization of pB‐DOX The Reactive oxygen species (ROS)-responsive prodrug Doxorubicin prodrug (pB-DOX) was synthesized through a TEA-catalyzed reaction between p-nitrobenzoyl-activated 4-(hydroxymethyl) phenylboronic acid pinacol ester and Doxorubicin hydrochloride (DOX·HCl) (Scheme 1a), and its structure and purity were verified by 1 H NMR (Additional file 1: Figure S1)
To explore the ROS-responsive capability of the prodrug, pB-DOX was incubated with different concentrations of Hydrogen peroxide (H2O2), and its activation rates were monitored by measuring the pB-DOX concentrations at different time periods
Summary
Chemotherapy, as a mainstay in clinical cancer treatment, shows severe systemic toxicity resulting from the nonspecific drug distribution in the human body [1, 2]. Stimuliresponsive DDSs release or activate anticancer drugs selectively in response to an internal stimulus in tumor microenvironments (TME) such as pH [6,7,8], glutathione (GSH) [9, 10], enzymes [11,12,13], reactive oxygen species (ROS) [14], and their combinations [15,16,17] Because both cancer and normal cells have endosomes/lysosomes with acidic pH [18] and high intracellular concentrations of GSH (2 × 10− 3 to 10 × 10− 3 M) [19], the widely reported pH- and GSH-based responsive DDSs offer limited selectivity. We designed a nanosystem combined photodynamic therapy (PDT) and ROS-responsive chemotherapy
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