Gradient Redox-Responsive and Two-Stage Rocket-Mimetic Drug Delivery System for Improved Tumor Accumulation and Safe Chemotherapy.

Recent drug delivery nanosystems for cancer treatment still suffer from the poor tumor accumulation and low therapeutic efficacy due to the complex in vivo biological barriers. To resolve these problems, in this work, a novel gradient redox-responsive and two-stage rocket-mimetic drug nanocarrier is designed and constructed for improved tumor accumulation and safe chemotherapy. The nanocarrier is constructed on the basis of the disulfide-doped organosilica-micellar hybrid nanoparticles and the following dual-functional modification with disulfide-bonded polyethylene glycol (PEG) and amido-bonded polyethylenimine (PEI). First, prolonged circulation duration in the bloodstream is guaranteed due to the shielding of the outer PEG chains. Once the nanocarrier accumulates at the tumoral extracellular microenvironment with low glutathione (GSH) concentrations, the first-stage redox-responsive behavior with the separation of PEG and the exposure of PEI is triggered, leading to the improved tumor accumulation and cellular internalization. Furthermore, with their endocytosis by tumor cells, a high concentration of GSH induces the second-stage redox-responsiveness with the degradation of silsesquioxane framework and the release of the encapsulated drugs. As a result, the rocket-mimetic drug carrier displays longer circulation duration in the bloodstream, higher tumor accumulation capability, and improved antitumor efficacy (which is 2.5 times higher than that with inseparable PEG). It is envisioned that the rocket-mimetic strategy can provide new solutions for improving tumor accumulation and safety of nanocarriers in further cancer chemotherapy.

Microfluidics Fabrication of Micrometer-Sized Hydrogels with Precisely Controlled Geometries for Biomedical Applications.

Micrometer-sized hydrogels are cross-linked three-dimensional network matrices with high-water contents and dimensions ranging from several to hundreds of micrometers. Due to their excellent biocompatibility and capability to mimic physiological microenvironments in vivo, micrometer-sized hydrogels have attracted much attention in the biomedical engineering field. Their biological properties and applications are primarily influenced by their chemical compositions and geometries. However, inhomogeneous morphologies and uncontrollable geometries limit traditional micrometer-sized hydrogels obtained by bulk mixing. In contrast, microfluidic technology holds great potential for the fabrication of micrometer-sized hydrogels since their geometries, sizes, structures, compositions, and physicochemical properties can be precisely manipulated on demand based on the excellent control over fluids. Therefore, micrometer-sized hydrogels fabricated by microfluidic technology have been applied in the biomedical field, including drug encapsulation, cell encapsulation, and tissue engineering. This review introduces micrometer-sized hydrogels with various geometries synthesized by different microfluidic devices, highlighting their advantages in various biomedical applications over those from traditional approaches. Overall, emerging microfluidic technologies enrich the geometries and morphologies of hydrogels and accelerate translation for industrial production and clinical applications.

Upconversion Nanoparticle-Based Organosilica-Micellar Hybrid Nanoplatforms for Redox-Responsive Chemotherapy and NIR-Mediated Photodynamic Therapy.

Upconversion nanoparticles (UCNPs) can convert near-infrared light (NIR, 980 or 808 nm) to ultraviolet (UV) or visible light, which can be widely used to improve tissue penetration depth in photodynamic therapy (PDT). Herein, we develop a kind of UCNP-based organosilica-micellar hybrid nanoplatform for redox-responsive chemotherapy and NIR-mediated PDT. The nanoplatform was constructed by the self-assembly of block copolymers polystyrene-b-poly (acrylic acid) and oil-soluble UCNPs in the oil/water system and the subsequent organosilica coating with 3-mercaptopropyltrimethoxysilane molecules. To endow the nanosystem with more stability in biological media, polyethylene glycol molecules were further modified via the Michael addition reaction. As a promising nanocarrier, chlorin e6 (Ce6) and doxorubicin (DOX) molecules were loaded into the hydrophobic core and the disulfide-doped organosilica shell, respectively. With endocytosis by SMMC-7721 tumor cells, the Ce6 and DOX coloaded nanosystem was activated by UCNPs through luminescence resonance energy transfer under the irradiation of 808 nm laser, thus generating cytotoxic 1O2 for NIR-mediated PDT. Meanwhile, DOX was selectively released because of the redox-responsive biodegradation of the disulfide-doped organosilica shell in the glutathione over-expressed SMMC-7721 tumor cells. Based on these, the chemotherapy/PDT combination toxic feature of the multifunctional nanosystem was further demonstrated in the DOX-resistant MCF-7 tumor cells. On the other hand, the Ce6 and DOX coloaded nanosystem exhibited negligible toxicity to the normal 3T3 cell because of the protective effects of organosilica coating. We envision that the resultant hybrid nanoplatform provides us a promising nanocarrier for the combination therapy of redox-responsive safe chemotherapy and efficient NIR-mediated PDT.