A stimuli-responsive, biodegradable, and dual drug-loaded hydrogel delivery system was formed in situ for combination drug therapy of cancer in vivo.

Cisplatin (CDDP) has been considered as one of the most effective anticancer drugs against cervical cancer, but the lack of selectivity of CDDP to tumor tissues often leads to serious toxic side effects. In this study, CDDP-incorporated Cy5.5-PEG- g-A-HA nanoparticles were prepared to endue CDDP the ability to selectively target tumors and fluorescence imaging in vivo. The nanoparticles exhibited a spherical shape with particle sizes between 216.4 and 281.5 nm and had a pH and Cl concentration dependence on controlled and sustained CDDP release, which was favorable for nanoparticles to release more drugs at acidic tumor microenvironment. Cell biology experiments demonstrated that the nanoparticles had good biocompatibility and tumor targeting; the nanoparticles could selectively bind and internalize into HeLa cells and induce apoptosis, but lead to less cytotoxicity on NIH3T3 cells. What is more, the nanoparticles could be clearly fluorescent-imaged in vivo and showed an effective accumulation at the tumor site. Antitumor test in vivo displayed that the nanoparticles had good antitumor efficiency and low systemic toxicity which improved the life quality of mice. Hence, the CDDP-incorporated Cy5.5-PEG- g-A-HA nanoparticles were a potential delivery system for targeting delivery of CDDP against cervical cancer.

Multiresponsive and biocompatible self-healing ε-PL/A-Pul/BPEI hydrogels were prepared in aqueous solution by Schiff base reaction with aldehyded pullulan (A-Pul), ε-poly-l-lysine (ε-PL) and branched polyethyleneimine (BPEI) as materials. The imine bonds were rapidly cross-linked into a hydrogel network within 80 s. Scanning electron microscopy images showed that the hydrogels exhibited a cross-linked structure with the average pore size from 58 to 82 μm. Rheology tests indicated that the hydrogels maintained good mechanical properties. Water contact angles and swelling studies suggested that the hydrogels could swell in water, with a max swell ratio of 1559%, and pH and temperature had an influence on the equilibrium swelling ratio. The hydrogels could be injected either before or after gelation, and they displayed a self-healing process in ddHO at room temperature based on the dynamic uncoupling and recoupling of the imine bonds. The MTT assays implied that the hydrogels were non-cytotoxic on mice bone marrow mesenchymal stem cells. Therefore, the hydrogels showed potential application in biomedical fields, and consequently further work was performed using the self-healing hydrogels as drug carriers in in vitro/vivo antitumor studies.

Ferroptosis is an alternative strategy to overcome chemoresistance, but effective therapeutic approaches to induce ferroptosis for acute myeloid leukemia (AML) treatment are limited. Here, we developed glutathione (GSH)-responsive cysteine polymer-based ferroptosis-inducing nanomedicine (GCFN) as an efficient ferroptosis inducer and chemotherapeutic drug nanocarrier for AML treatment. GCFN depleted intracellular GSH and inhibited glutathione peroxidase 4, a GSH-dependent hydroperoxidase, to cause lipid peroxidation and ferroptosis in AML cells. Furthermore, GCFN-loaded paclitaxel (PTX@GCFN) targeted AML cells and spared normal hematopoietic cells to limit the myeloablation side effects caused by paclitaxel. PTX@GCFN treatment extended the survival of AML mice by specifically releasing paclitaxel and simultaneously inducing ferroptosis in AML cells with restricted myeloablation and tissue damage side effects. Overall, the dual-functional GCFN acts as an effective ferroptosis inducer and a chemotherapeutic drug carrier for AML treatment.

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Aldehyde hyaluronic acid-cisplatin (A-HA-CDDP) complex nanoparticles were readily prepared, and CDDP was stably loaded into the core of the NPs through imine bond and coordinate bond linkages. The results show that the NPs were prepared successfully by a chemical complexation reaction rather than by physical mixing. Compared to many CDDP and HA complex nanoparticles evaluated in other studies, A-HA-CDDP NPs with imine and coordinate bonds between the A-HA and CDDP displayed better sustained release behavior and pH sensitivity. Therefore, the acidic tumor environment could accelerate the release of CDDP from the NPs. MTT and AO/EB staining assays showed that A-HA-CDDP NPs had comparable cell inhibition with CDDP in HeLa cells as well as little toxicity to NIH3T3 cells. This result indicates that the chemical reaction between A-HA and CDDP had little effect on the antitumor activity of CDDP and that the NPs actively targeted CD44-rich tumor cells. Both a hemolysis test and a protein adsorption assay demonstrated that A-HA-CDDP NPs had good biocompatibility and blood circulation in vivo. Therefore, the NPs have the potential to be used for targeted CDDP delivery in vivo. A subsequent publication will describe the circulation, targeting and tumor inhibition experiments of these NPs in vivo.

In the past decade, a variety of cysteine-based multifunctional biomaterials has been successfully developed for drug delivery and proven invaluable in campaigns against human disease. Despite several significant achievements, a systematic investigation of the structure-property relationships in the field of drug delivery has not been performed. In this review, a variety of up-to-date literature results are discussed and compiled in which cysteine and its derivatives have been used in the preparation of payload delivery systems for the treatment of human disease. Particular emphasis is placed on the synthesis methods, especially the structure-property relationship for drug delivery and disease therapy. Additionally, this review focuses on recent innovations in redox-responsive nanocarriers based on cysteine and its derivatives for in vivo drug delivery to achieve a better therapeutic effect. In summary, nanocarriers based on cysteine and its derivatives have the potential to enhance the efficiency of human disease therapy without increasing toxicity.

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