Hyperbranched polyester-based fluorescent probe for histone deacetylase via aggregation-induced emission.

Aberrant expression of histone deacetylases (HDACs) is related to various types of cancer and is associated with increased proliferation of tumor cells. Hence, the detection of HDAC activities is of great significance for medical sciences as well as biological diagnostics. Herein, we report a hyperbranched polyester-based one-step fluorescent assay for HDAC. This assay system consists of two water-soluble components: the hyperbranched polyester coupled with the acetylated lysine groups (H40-Lys(Ac)) and the negatively charged TPE derivative bearing two sulfonic acid groups (TPE-2SO3(-)). HDAC triggers the deacetylation of H40-Lys(Ac), thereby turning the electroneutral polymer into the positively charged one. Consequently, complexation occurs between the positively charged polymer and the negatively charged TPE-2SO3(-), thereby leading to the formation of nanoaggregates due to electrostatic interaction. Eventually, the fluorescence enhancement as a result of AIE effect is achieved. This assay system is operable in aqueous media with very low detection limit of 25 ng/mL. The system is capable of detecting HDAC in such biological fluid as serum, and this strategy may provide a new and effective approach for enzyme assay.

High Loading of Hydrophobic and Hydrophilic Agents via Small Immunostimulatory Carrier for Enhanced Tumor Penetration and Combinational Therapy.

Development of small-sized nanoformulations for effective tumor penetration, particularly for those tumors with dense stroma is a major challenge in cancer nanomedicine. It is even more challenging to achieve effective co-loading of both hydrophobic and hydrophilic anticancer agents through a small-sized nanocarrier. In this work, we designed a novel redox-responsive gemcitabine (GEM)-conjugated polymer POEG-co-PVDGEM (PGEM) as a small-sized nanocarrier to co-deliver hydrophilic GEM and hydrophobic paclitaxel (PTX). Methods: The in vitro physicochemical and biological properties of PTX/PGEM NPs were characterized. The efficiency of the PGEM carrier in selective codelivery of GEM and PTX in two murine tumor models as well as a patient derived xenograft model (PDX) was also evaluated. In addition, we investigated the changes in tumor immune microenvironment after treatment with PTX/PGEM nanoparticles. Results: We discovered that GEM conjugation could significantly decrease the nanoparticle size from 160 nm to 13 nm. Moreover, different from most reported GEM-conjugated polymers, PGEM polymer could serve as a prodrug carrier to load a wide variety of hydrophobic agents with high drug loading capacity and excellent stability. More importantly, our strategy could be extended to various nucleotides-based drugs such as azacytidine, decitabine and cytarabine, suggesting a new platform for co-delivery of various first line hydrophilic and hydrophobic anticancer agents. Imaging showed that our small-sized carrier was much more effective in tumor accumulation and penetration compared to the relatively large-sized drug carrier. The PGEM prodrug-based carrier not only well retained the pharmacological activity of GEM, but also boosted T-cell immune response. Furthermore, delivery of PTX via PGEM led to significantly improved antitumor activity in several murine cancer models and a PDX model of colon cancer. Conclusion: This work not only provided a small-sized carrier platform that was able to load multiple hydrophilic and hydrophobic drugs with high loading capacity, but also provided an effective regimen for enhanced tumor penetration and improved anti-tumor immunity.