Glutathione-Responsive Carboxymethyl Chitosan Nanoparticles for Controlled Release of Herbicides

Glutathione-responsive carboxymethyl chitosan nanoparticles cross-linked with disulfide bonds were developed for controlled release of herbicides. The nanoparticles were synthesized by selfassembly of amphiphilic carboxymethyl chitosan derivative (CMCS-MUA) in aqueous solution and subsequently producing disulfide cross-linking bonds by ultrasonic treatment. TEM showed that the nanoparticles had a spherical core-shell configuration with a size of about 250 nm. Assessment of stability of the nanoparticles (considering mean diameter, polydispersity, and Zeta potential) was conducted over a period of three months, and the nanoparticles were found to be stable in solution. Herbicide-loaded nanoparticles were prepared using diuron as a model herbicide. In vitro release study revealed that diuron can be released from nanoparticles in a controlled manner depended on the glutathione concentration. Herbicidal activity assays performed with preemergence treatment of target species (Echinochloa crusgalli) showed the effectiveness of diuron- loaded nanoparticles. Assays with nontarget species (Zea mays) showed that the diuronloaded nanoparticles did not affect plant growth. The results indicate that the glutathioneresponsive nanoparticles prepared in this work will be a promising candidate for controlled release of herbicides in agriculture.

Inclusion-Interaction Assembly Strategy for Constructing pH/Redox Responsive Micelles for Controlled Release of 6-Mercaptopurine

An inclusion-interaction assembly strategy was used to construct novel pH/redox responsive core-shell micelles with hydrophobic drug as the core and hydrophilic polymer as the shell. At first, a dimer of hydrophobic drug 6-mercaptopurine and a hydrophilic β-CD grafted carboxymethyl chitosan were synthesized. Then, a novel amphiphilic inclusion complex was prepared with the dimer being partially embedded into the cavity of β-CD moiety. It self-assembled into pH/redox responsive core-shell micelles in distilled water. TEM confirmed that the micelles possessed a spherical core-shell configuration with a mean size of about 160 nm. DLS showed that the micelles were stable in aqueous solution. Their particle diameters altered with pH values as well as glutathione (GSH) concentrations and respectively attained a maximum value at pH 6.0 and 20 mM GSH. Release profiles of 6-mercaptopurine showed a low release rate (about 27 wt% after 48 h) in pH 7.4 medium with 10 μM GSH, and a marked increase (over 88 wt% after 48 h) in pH 5.0 medium with 20 mM GSH. In vitro cytotoxicity test showed that the micelles had a dose-dependent toxicity for HeLa cells, indicating a great potential for controlled release of 6-mercaptopurine in tumor cells.

Anti-PD-L1/TGF-BR fusion protein (SHR-1701) overcomes disrupted lymphocyte recovery-induced resistance to PD-1/PD-L1 inhibitors in lung cancer

Background:Second-generation programmed cell death-protein 1/pro-grammed death-ligand 1(PD-1/PD-L1)inhibitors,such as bintrafusp alfa(M7824),SHR-1701,and YM101,have been developed to simultaneously block PD-1/PD-L1 and transforming growth factor-beta/transforming growth factor-beta receptor(TGF-P/TGF-βR).Consequently,it is necessary to identify predictive factors of lung cancer patients who are not only resistant to PD-1/PD-LI inhibitors but also sensitive to bifunctional drugs.The purpose of this study was to search for such predictors.Methods:Multivariable Cox regression was used to study the association between the clinical outcome of treatment with PD-1/PD-L1 inhibitors and lym-phocyte recovery after lymphopenia in lung cancer patients.Murine CMT167 lung cancer cells were engineered to express the firefly luciferase gene and implanted orthotopically in the lung of syngeneic mice.Bioluminescence imag-ing,flow cytometry,and immunohistochemistry were employed to detrmine response to immunotherapy and function of tumor-infiltrating immune cells.Results:For lung cancer patients treated with anti-PD-1/PD-LI antibodies,poor lymphocyte recovery was associated with a shorter progression-free survival(PFS;P<0.001),an accumulation of regulatory T cells(Tregs),and an elimi-nation of CD8+T cells in the peripheral blood.Levels of CD8+T cells and Treg cells were also imbalanced in the tumors and peripheral immune organs of mice with poor lymphocyte recovery after chemotherapy.Moreover,these mice failed to respond to anti-PD-1 antibodies but remained sensitive to the anti-PD-LI/TGF-βR fusion protein(SHR-1701).Consistently,SHR-1701 but not anti-PD-1 antibod-ies,markedly enhanced IFN-γproduction and Ki-67 expression in peripheral CD8+T cells from patients with impaired lymphocyte recovery.Conclusions:Lung cancer patients with poor lymphocyte recovery and suffer-ing from persistent lymphopenia after previous chemotherapy are resistant to anti-PD-1/PD-L1 antibodies but might be sensitive to second-generation agents such as SHR-1701.