Prodrug Nanomedicine Inhibits Chemotherapy-Induced Proliferative Burst by Altering the Deleterious Intercellular Communication.

Chemotherapy is one of the most commonly used clinical antitumor strategies. However, the therapy-induced proliferative burst, which always accompanies drug resistance and metastasis, has become a major obstacle during treatment. Except for some endogenous cellular or genetic mechanisms and some microenvironmental selection pressures, the intercellular connections in the tumor microenvironment (TME) are also thought to be the driving force for the acquired drug resistance and proliferative burst. Even though some pathway inhibitors or cell exempting strategies could be applied to partially avoid these unwanted communications, the complexity of the TME and the limited knowledge about those unknown detrimental connections might greatly compromise the efforts. Therefore, a more broad-spectrum strategy is urgently needed to relieve the drug-induced burst proliferation during various treatments. In this article, based on the possible discrepancies in metabolic activity between cells with different growth rates, several ester-bond-based prodrugs were synthesized. After screening, 7-ethyl-10-hyodroxycamptothecin-based prodrug nanoparticles were found to efficiently overcome the paclitaxel resistance, to selectively act on the malignantly proliferated drug-resistant cells and, furthermore, to greatly diminish the proliferative effect of common cytotoxic agents by blocking the detrimental intercellular connections. With the discriminating ability against malignant proliferating cells, the as-prepared prodrug nanomedicine exhibited significant anticancer efficacy against both drug-sensitive and drug-resistant tumor models, either by itself or by combining with highly potent nonselective chemotherapeutics. This work provides a different perspective and a possible solution for the treatment of therapy-induced burst proliferation.

Reduction-sensitive platinum (IV)-prodrug nano-sensitizer with an ultra-high drug loading for efficient chemo-radiotherapy of Pt-resistant cervical cancer in vivo.

Cisplatin is widely used in the chemoradiotherapy (CRT) of cervical cancers. However, despite the severe systemic side effects, the therapeutic efficacy of cisplatin is often compromised by the development of drug resistance, which is closely related to the elevated intracellular thiol-containing species (especially glutathione (GSH)) and the adenosine triphosphate (ATP)-dependent glutathione S-conjugate pumps. The construction of a safe and redox-sensitive nano-sensitizer with high disulfide density and high Pt(IV) prodrug loading capacity (up to 16.50% Pt and even higher), as described herein, is a promising way to overcome the cisplatin resistance and enhance the CRT efficacy. The optimized nanoparticles (NPs) (referred to as SSCV5) with moderate Pt loading (7.62% Pt) and median size (c.a. 40 nm) was screened out and used for further biological evaluation. Compared with free cisplatin, more drugs could be transported and released inside the cisplatin resistant cells (Hela-CDDP) by SSCV5 NPs. With the synergistic effect of GSH scavenging and mitochondrial damage, SSCV5 NPs can easily reverse the cisplatin resistance. Moreover, the higher nucleus DNA binding Pt content of SSCV5 NPs not only caused the DNA damage and apoptosis of Hela-CDDP cells but also sensitized these cells to X-Ray radiation. The in vivo safety and efficacy results showed that SSCV5 NPs effectively accumulated inside tumor and inhibited the growth of cisplatin resistant xenograft models while alleviating the serious side effect associated with cisplatin (the maximum tolerated cisplatin equivalent of single injection is higher than 20 mg/kg body weight). The intervention of exogenous radiation further improved the anticancer efficacy of SSCV5 NPs and caused the shrinkage of tumor volume, thus making this safe and facile nano-sensitizer a promising route for the neoadjuvant CRT of cervical cancers.

CD44-Targeted Facile Enzymatic Activatable Chitosan Nanoparticles for Efficient Antitumor Therapy and Reversal of Multidrug Resistance.

Nanoparticles are attractive platforms for the delivery of various anticancer therapeutics. Nevertheless, their applications are still limited by the relatively low drug loading capacity and the occurrence of multidrug resistance (MDR) against chemotherapeutics. In this study, we report that the integration of d-α-tocopherol succinate (VES) residue with both chitosan and paclitaxel (PTX) led to significant improvement of drug loading capacity and drug loading efficiency through the enhancement of drug/carrier interaction. After the incorporation of hyaluronic acid containing PEG side chains (HA-PEG), higher serum stability and more efficient cellular uptake were obtained. Due to HA coating, VES residues and the enzymatic responsive drug release property, such facile nanoparticles actively targeted cancer cells that overexpress CD44 receptor and efficiently reversed the MDR of treated cells, but caused no significant toxicity to mouse fibroblast (NIH-3T3). More importantly, with HA-PEG coating, longer blood circulation and more effective tumor accumulation were achieved for prodrug nanoparticles. Finally, superior anticancer activity and excellent safety profile was demonstrated by HA-PEG coated enzymatically activatable prodrug nanoparticles compared to commercially available Taxol formulation.