A pH/ROS Cascade‐Responsive Charge‐Reversal Nanosystem with Self‐Amplified Drug Release for Synergistic Oxidation‐Chemotherapy

Abstract

Poor cell uptake of drugs is one of the major challenges for anticancer therapy. Moreover, the inability to release adequate drug at tumor sites and inherent multidrug resistance (MDR) may further limit the therapeutic effect. Herein, a delivery nanosystem with a charge‐reversal capability and self‐amplifiable drug release pattern is constructed by encapsulating β‐lapachone in pH/ROS cascade‐responsive polymeric prodrug micelle. The surface charge of this micellar system would be converted from negative to positive for enhanced tumor cell uptake in response to the weakly acidic tumor microenvironment. Subsequently, the cascade‐responsive micellar system could be dissociated in a reactive oxygen species (ROS)‐rich intracellular environment, resulting in cytoplasmic release of β‐lapachone and camptothecin (CPT). Furthermore, the released β‐lapachone is capable of producing ROS under the catalysis of nicotinamide adenine dinucleotide (NAD)(P)H:quinone oxidoreductase‐1 (NQO1), which induces the self‐amplifiable disassembly of the micelles and drug release to consume adenosine triphosphate (ATP) and downregulate P‐glycoprotein (P‐gp), eventually overcoming MDR. Moreover, the excessive ROS produced from β‐lapachone could synergize with CPT and further propagate tumor cell apoptosis. The studies in vitro and in vivo consistently demonstrate that the combination of the pH‐responsive charge‐reversal, upregulation of tumoral ROS level, and self‐amplifying ROS‐responsive drug release achieves potent antitumor efficacy via the synergistic oxidation‐chemotherapy.

Bioresponsive Nanomedicine: The Next Step of Deadliest Cancers' Theranostics

“…As other major factors, the concentrations of reactive oxygen species (ROS) and glutathione (GSH) are extremely higher in TME (Cook et al, 2004), which allow different nano-agents to be applied for treating aggressive cancers including taxane resistant prostate cancer, erlotinib-resistant EGFR-mutated NSCLC cells and TNBC via redox-induced therapeutic functions (He et al, 2018;Dai et al, 2019;Hu et al, 2019;Lin et al, 2019;Liu et al, 2019b;Yang et al, 2019a;Zhang et al, 2019;Gao et al, 2020). In the combination of acidic and GSH sensitive features, a novel P-RUB micelle was designed for co-delivering docetaxel (DTX) and rubone (RUB) in fighting taxane resistant prostate cancer (PC3-TXR) .…”

Fabrication of smart polymeric nanovectors to amplify intracellular oxidative stress for chemodynamic therapy

“…如Tang, Gao和Rao等 [49] 图 2 cRGD和三苯基磷(TPP)功能化的聚前药两亲分子自组装为胶束纳米粒子用于CT和CDT协同治疗 [46] (网络版彩图) 化疗药物和ROS生成剂被用于提升CT/CDT治疗效 果 [52] . 为了进一步提高肿瘤细胞的选择性, 一些能够 促进纳米载体肿瘤组织靶向和细胞摄取的策略被整合 到这些ROS响应的体系中, 如引入主动靶向和电荷反 转基元等 [53] .…”

Dual-responsive doxorubicin-loaded nanomicelles for enhanced cancer therapy

“…Plenty of smart drug delivery systems have been proposed to improve the therapeutic e cacy and reduce undesirable side effects through achieving "on demand" drug release at tumor site under unique internal or external stimuli including pH gradient [1][2][3][4][5][6] , intracellular reductive agents [7,8] , peculiar enzymes [9,10] , ROS [11,12] , and so on. However, the stimuli levels of the tumor extracellular microenvironments are particularly subtle, such as relatively low ROS concentration even under pathological conditions, which accordingly imposes strict demand for the sensitivity of the materials responsive to the tumor microenvironments [13][14][15] . Besides, the poor uptake of tumor cells and incomplete drug release are extra two critical challenges hindering the clinical translation of polymeric drug [6,15] .…”

“…Tremendous efforts had been devoted to the development of stimuli-responsive tumor-targeted drug delivery systems to deal with aforementioned dilemma. On one hand, pH-dependent charge conversion strategy is utilized to construct polymeric drug, which maintains their stealth features during circulation and then undergoes a charge reversal process for achieving enhanced tumor cells' internalization once exposed to tumor relative acidic environment [15][16][17][18] . On the other hand, polymeric drug with ROS generation capability will be an effective approach to copying with insu cient ROS concentration for activating the complete drug release [13][14][15]19] .…”

“…The pH-dependent charge reversal delivery systems remained negatively charged under physiological environment (pH 7.2~7.4), which facilitates reduced nonspeci c interactions with serum components. Under tumor microenvironment (pH 6.2~6.9), they are converted to positive charge, achieving charge reversal to enhance targeted tumor uptake [6,15] . Secondly, TOS, an analogue of vitamin E, rapidly generates ROS in cells after interacting with mitochondrial respiratory complex II and interfering the electron transportation chain in mitochondria [13] .…”