Tumor-Adhesive and pH-Degradable Microgels by Microfluidics and Photo-Cross-Linking for Efficient Antiangiogenesis and Enhanced Cancer Chemotherapy.

Tumor angiogenesis with the vascular network formation provides nutrition and oxygen for cancer cells, promoting the proliferation and metastasis of malignant tumors. Bevacizumab (Bev) as an efficient antiangiogenic antibody is able to normalize the tumor vasculature with better blood flow and reduced interstitial fluid pressure, allowing drugs with more uniform distribution and deeper penetration into the tumor; however, it is highly difficult to realize the simultaneous delivery of Bev and anticancer drugs localized at the tumor tissue. Here, we prepared tumor-adhesive and pH-degradable poly(vinyl alcohol) (PVA) microgels for tumor-localized delivery of Bev and docetaxel (DTX), to achieve efficient antiangiogenesis and enhanced cancer chemotherapy. PVA microgels (∼200 µm) decorated with tissue-adhesive dopamine (DA) moieties were fabricated by a combination of high-throughput microfluidics technology and photo-cross-linking chemistry with a considerable coencapsulation efficiency for Bev and DTX. PVA microgels exhibited sustained drug release at the tumoral acidic conditions as the microgel degradation, and DA moieties on the microgels facilitated Bev with long retention at the tumor tissue, highly blocking the vascular endothelial growth factor (VEGF) and inhibiting tumor angiogenesis, as compared to free Bev or no DA-decorated microgels. In addition, the antitumor activity on the 4T1-Luc breast tumor mouse model treated with Bev/DTX-coloaded microgels showed obviously superior tumor growth inhibition than the other treatment groups, in which the combinational therapy efficacy of Bev and DTX mediated by the tumor-adhesive microgels was further confirmed by the immunohistochemistry (IHC) analysis. These PVA microgels with efficient antiangiogenesis and enhanced cancer chemotherapy provide a highly potential platform to treat different malignant tumors as well as the recurrent and metastatic tumors.

Mechanically-Compliant Bioelectronic Interfaces through Fatigue-Resistant Conducting Polymer Hydrogel Coating.

Because of their distinct electrochemical and mechanical properties, conducting polymer hydrogels have been widely exploited as soft, wet, and conducting coatings for conventional metallic electrodes, providing mechanically compliant interfaces and mitigating foreign body responses. However, the long-term viability of these hydrogel coatings is hindered by concerns regarding fatigue crack propagation and/or delamination caused by repetitive volumetric expansion/shrinkage during long-term electrical interfacing. This study reports a general yet reliable approach to achieving a fatigue-resistant conducting polymer hydrogel coating on conventional metallic bioelectrodes by engineering nanocrystalline domains at the interface between the hydrogel and metallic substrates. It demonstrates the efficacy of this robust, biocompatible, and fatigue-resistant conducting hydrogel coating in cardiac pacing, showcasing its ability to effectively reduce the pacing threshold voltage and enhance the long-term reliability of electric stimulation. This study findings highlight the potential of its approach as a promising design and fabrication strategy for the next generation of seamless bioelectronic interfaces.

Engineering Electrodes with Robust Conducting Hydrogel Coating for Neural Recording and Modulation.

Coating conventional metallic electrodes with conducting polymers has enabled the essential characteristics required for bioelectronics, such as biocompatibility, electrical conductivity, mechanical compliance, and the capacity for structural and chemical functionalization of the bioelectrodes. However, the fragile interface between the conducting polymer and the electrode in wet physiological environment greatly limits their utility and reliability. Here, a general yet reliable strategy to seamlessly interface conventional electrodes with conducting hydrogel coatings is established, featuring tissue-like modulus, highly-desirable electrochemical properties, robust interface, and long-term reliability. Numerical modeling reveals the role of toughening mechanism, synergy of covalent anchorage of long-chain polymers, and chemical cross-linking, in improving the long-term robustness of the interface. Through in vivo implantation in freely-moving mouse models, it is shown that stable electrophysiological recording can be achieved, while the conducting hydrogel-electrode interface remains robust during the long-term low-voltage electrical stimulation. This simple yet versatile design strategy addresses the long-standing technical challenges in functional bioelectrode engineering, and opens up new avenues for the next-generation diagnostic brain-machine interfaces.

Tumor localization of oncolytic adenovirus assisted by pH-degradable microgels with JQ1-mediated boosting replication and PD-L1 suppression for enhanced cancer therapy.

Oncolytic therapy is a fast-developing cancer treatment field based on the promising clinical performance from the selective tumor cell killing and induction of systemic antitumor immunity. The virotherapy efficacy, however, is strongly hindered by the limited virus propagation and negative immune regulation in the tumor microenvironments. To enhance the antitumor activity, we developed injectable pH-degradable PVA microgels encapsulated with oncolytic adenovirus (OA) by microfluidics for localized OA delivery and cancer treatments. PVA microgels were tailored with an OA encapsulation efficiency of 68% and exhibited a pH-dependent OA release as the microgel degradation at mildly acidic conditions. PVA microgels mediated fast viral release and increased replication in HEK293T and A549 cells at a lower pH, and the replication efficiency could be further reinforced by co-loading with one BET bromodomain inhibitor JQ1, inducing significant cytotoxicity against A549 cells. An in vivo study revealed that OA release was highly located at the tumor tissue assisted by PVA microgels, and the OA infection was also enhanced with the addition of JQ1 treatment, meanwhile greatly inhibiting the PD-L1 expression to overcome the immune suppression. OA/JQ1 co-encapsulated injectable microgels exhibited a superior in vivo antitumor activity on the A549 lung tumor-bearing mice by the combination of inhibited proliferation, amplified oncolysis, and potential immune regulation.

Folated pH-degradable nanogels for the simultaneous delivery of docetaxel and an IDO1-inhibitor in enhancing cancer chemo-immunotherapy.

Combining chemotherapy and immunotherapy has been considered as an attractive approach to improve cancer therapy. Here we prepared folated PVA-based nanogels for the simultaneous delivery of docetaxel (DTX) and the indoleamine 2,3-dioxygenase 1 (IDO1) inhibitor NLG919 (N9) for enhancing cancer chemo-immunotherapy. FDA-approved poly(vinyl alcohol) (PVA) with good biocompatibility was modified with vinyl ether acrylate (VEA) groups for UV-crosslinking and acidic degradation. Carboxyl groups were introduced via modification with succinic anhydride for improved drug loading and folic acid (FA) ligands were incorporated for tumor targeting. UV-crosslinked folated PVA nanogels were efficiently taken up by tumor cells followed by endo/lysosomal pH-triggered intracellular drug release, which induced significant cytotoxicity towards 4T1 breast cancer cells in vitro. DTX and N9 co-loaded PVA nanogels exhibited a much higher antitumor efficiency in 4T1 mouse breast cancer models in vivo as compared to the free drug controls. The drug-laden nanogels not only directly killed the tumor cells by DTX, but also induced immunogenic cell death (ICD) promoting intratumoral accumulation of cytotoxic T lymphocytes, and further combining with N9 elevated the intratumoral infiltration of CD8+ T cells and NK cells and inhibited the infiltration of MDSCs, downregulating IDO1-mediated immunosuppression.