With the use of ammonia borane as a hydrogen source, a borane catalyzed metal-free transfer hydrogenation of pyridines was successfully realized for the first time to furnish a variety of piperidines in 44-88% yields with moderate to excellent cis-selectivities. The ease in handling without requiring high pressure H makes this transfer hydrogenation practical and useful.

The hypoxic nature of solid tumors limits the efficacy of radiotherapy (RT) and leads to radiation resistance. Hypoxic radiosensitizers can enhance tumor radiosensitivity by mimicking the effects of oxygen, but their efficacy has been limited by the heterogeneous oxygen distribution in tumor tissue. Herein, a multimodal therapeutic nanoplatform fabricated by co-encapsulation of chlorin e6 and tirapazamine (TPZ) with an amphiphilic polymeric conjugate of cisplatin (CDDP) and metronidazole is reported. This platform could kill the tumor periphery cells by the deeply penetrated oxygen-consuming sonodynamic therapy and unify the heterogeneously hypoxic context simultaneously, which then actuate the release and activation of the loaded TPZ. TPZ could further sensitize RT along with CDDP and metronidazole residues under the resultant hypoxic condition, which significantly decreases the radiation dosage required to cause massive cell damage. Except for the significantly suppressed tumor growth and metastasis caused by the multimodal therapeutic nanoplatform, its hypoxia-directed feature also endows it with excellent safety.

Meanwhile, the occurrence of undesirable side effects, low bioavailability, and emergence of drug resistance are also depleting the existing drug library. Considering the slow pace of new drug development, combination of two or more currently available drugs with non-overlapping systemic toxicities and different therapeutic mechanisms, [6] for example, the FOLFIRINOX regimen in advanced pancreatic cancer therapy, [7] which consists of 5-fluorouracil, leucovorin, irinotecan, and oxaliplatin, is recognized as the cornerstone of cancer therapy. The ideal combination therapy should be individualized, which means that the class and dosage of drug combinations should be customized for patients, [8] making the ratiometric delivery of multiple drugs a new trend. [9] However, distinct pharmacokinetics and biodistribution of different drugs make it impossible to control the optimal dosages and deliver a predefined drug ratio at the target tissue using the current combination regimens in clinical practice, which involves administration of free drug mixture and offers little flexibility for treatment optimization. [10] In contrast to the administration of free drug mixture, nanocarrier-based combination therapy has many advantages, [11] for example, co-encapsulation of both soluble and poorly soluble drugs, co-delivery of small molecular drugs and macro molecular agents, [12] drug protection, cellular uptake of nanoparticles (NPs) via endocytosis, and passive tumor accumulation. [13] Compared to co-administration of NPs, co-delivery of multiple drugs using a single NP is preferred due to its ability to achieve synergistic therapeutic effect and reduce drug resistance, [10a,14] and unify the pharmacokinetics and biodistribution of different drug molecules, leading to dosage optimization in vivo. The concurrent delivery of multiple free drugs for combination chemotherapy using a single vehicle, such as liposomes, polymeric NPs, and other nanocarriers, has made tremendous progress. Several strategies have been employed to co-encapsulate multiple drugs into a single nanocarrier, including physical loading, surface conjugation, and covalent linkage, prior to NP synthesis. [15] A very recent macrocyclic-amphiphile-based NP platform has shown attractive benefits of ratiometric deliveryThe 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 ration...

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 broadspectrum 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.

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