Co-Delivery of Precisely Prescribed Multi-Prodrug Combination by an Engineered Nanocarrier enables Efficient Individualized Cancer Chemotherapy.

The limited anticancer drug library and the frequent occurrence of drug resistance have driven monotherapy-based cancer therapy into a difficult situation. Considering the formidable process of new drug discovery, combination therapy using currently available drugs is a potential alternative. Nevertheless, the barrier between in vitro combination screening and precise in vivo delivery remains insurmountable in the current free-drug- or nanoparticle (NP)-based combination therapy, which substantially hinders the application of combination therapy. Herein, a novel, precise drug delivery strategy to realize efficient and individualized combination therapy is proposed. Nanomedicine (NM) is engineered using a microfluidics-based mixer by combining rationally designed polymeric prodrugs of three commercial chemotherapeutics and a cascade-responsive block copolymer; the NM possesses ratiometric drug loading and synchronized drug release. In addition to quantitative drug loading and precisely controlled drug combination, consistent nanoproperties of these NPs make their in vivo fate predictable. Consequently, tumor growth and metastasis can be effectively inhibited by precisely prescribed NPs derived from in vitro combination screening. This proof-of-concept study clearly reveals the feasibility of overcoming the current drug-library limitations through precise delivery of any predetermined drug combination, facilitating translational research of individualized combination therapy.

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.