Fabrication of antibacterial poly (L-lactic acid)/tea polyphenol blend films via reactive blending using SG copolymer.

Poly (L-lactic acid) (PLLA) composite materials with both excellent antibacterial properties and mechanical properties are highly desirable for both food packaging and biomedical applications. However, a facile method to prepare transparent PLLA composite films with both excellent antibacterial and mechanical properties is still lacking. In this work, blend films based on PLLA, tea polyphenols (TP) and poly (styrene-co-glycidyl methacrylate) (SG) copolymers (PLLA/TP/SG) were prepared by melt blending using twin screw extruder. The blend films showed high transparency with a brownish color originated from tea polyphenols. Both SEM and DSC analyses confirmed that the blends are thermodynamically compatible. GPC and mechanical assessments demonstrated that the PLLA/TP binary blends exhibit reduced molecular weight and compromised mechanical properties, compared to neat PLLA. However, incorporating SG copolymer resulted in increased molecular weight and improved mechanical properties for the PLLA/TP/SG blends. The FT-IR spectra exhibited a shift to lower wavenumber for the absorption peak associated with the benzene ring on TPs after blending with PLLA and SG, indicating the occurrence of transesterification between PLLA and TP. Plate coating studies revealed that the PLLA/TP/SG blends with TP incorporation at 5 wt% exhibited a bacteriostatic rate of 99.99 % against Staphylococcus aureus and Escherichia coli. Overall, our study reveals that the PLLA/TP/SG blend films exhibit excellent antibacterial properties coupled with good mechanical properties, rendering them a promising candidate for antibacterial packaging materials.

Bioinspired Lipoproteins of Furoxans-Gemcitabine Preferentially Targets Glioblastoma and Overcomes Radiotherapy Resistance.

Radiotherapy (RT) resistance is an enormous challenge in glioblastoma multiforme (GBM) treatment, which is largely associated with DNA repair, poor distribution of reactive radicals in tumors, and limited delivery of radiosensitizers to the tumor sites. Inspired by the aberrant upregulation of RAD51 (a critical protein of DNA repair), scavenger receptor B type 1 (SR-B1), and C-C motif chemokine ligand 5 (CCL5) in GBM patients, a reduction-sensitive nitric oxide (NO) donor conjugate of gemcitabine (RAD51 inhibitor) (NG) is synthesized as radio-sensitizer and a CCL5 peptide-modified bioinspired lipoprotein system of NG (C-LNG) is rationally designed, aiming to preferentially target the tumor sites and overcome the RT resistance. C-LNG can preferentially accumulate at the orthotopic GBM tumor sites with considerable intratumor permeation, responsively release the gemcitabine and NO, and then generate abundant peroxynitrite (ONOO- ) upon X-ray radiation, thereby producing a 99.64% inhibition of tumor growth and a 71.44% survival rate at 120 days in GL261-induced orthotopic GBM tumor model. Therefore, the rationally designed bioinspired lipoprotein of NG provides an essential strategy to target GBM and overcome RT resistance.

Autophagy inhibition recovers deficient ICD-based cancer immunotherapy.

ICD effect is usually accompanied with robust autophagy that can depredate immune-associated antigens in tumors, thereby weakening the immune response against tumor growth. To circumvent this dilemma, we combined an ICD inducer (Shikonin, SHK) with an autophagy inhibitor (hydroxychloroquine, HCQ) for colon cancer immunotherapy. Notably, HCQ boosted SHK-induced antigen exposure in colon cancer in vitro and in vivo. However, autophagy inhibition caused loss of ATP, which compromised antitumor immune response. Therefore, a compensatory strategy was employed by introducing ATP as a remote loading gradient of the liposome to encapsulate HCQ (LipHCQa). LipHCQa achieved an excellent antitumor efficiency without dampening the immune response. Furthermore, a systematic determination of the optimal dosage of combined LipSHK and LipHCQa suggested that autophagy inhibiting at an appropriate dosage level was beneficial for maximizing ICD-based antitumor immunity. This study proved that autophagy inhibitors can recover the deficient ICD-based antitumor immune response and present potential clinical applications for cancer immunotherapy.

Development of a series of novel Mcl-1 inhibitors bearing an indole carboxylic acid moiety.

The B cell lymphoma protein 2 (Bcl-2) family proteins regulate cell apoptosis by participating in the endogenous apoptosis pathway. As an important anti-apoptotic protein, Myeloid cell leukemia 1 (Mcl-1) is overexpressed in a variety of tumor cells, and targeting this protein has been a promising strategy for cancer therapy. Herein, based on the 1H-indole-5-carboxylic acid structure previously discovered, we have developed a series of novel compounds with increased affinities and selectivity toward Mcl-1 through structure-based drug design. Among those compounds, 26 exerted relatively better affinity and selectivity for Mcl-1 with moderate inhibition in HL-60 cells. Mechanism studies showed that compound 26 could induce cancer cells apoptosis in an Mcl-1-dependent manner. It also exhibited good microsomal and plasma stability with acceptable pharmacokinetics profiles. Furthermore, treatment with target compound in a 4T1 xenograft mouse model significantly suppressed the tumor growth. Overall, the small molecule described herein represents a promising Mcl-1 inhibitor for further study.