Kangyi Zhang

Diamond Nanogel-Embedded Contact Lenses Mediate Lysozyme-Dependent Therapeutic Release

Temporarily implanted devices, such as drug-loaded contact lenses, are emerging as the preferred treatment method for ocular diseases like glaucoma. Localizing the delivery of glaucoma drugs, such as timolol maleate (TM), can minimize adverse effects caused by systemic administration. Although eye drops and drug-soaked lenses allow for local treatment, their utility is limited by burst release and a lack of sustained therapeutic delivery. Additionally, wet transportation and storage of drug-soaked lenses result in drug loss due to elution from the lenses. Here we present a nanodiamond (ND)-embedded contact lens capable of lysozyme-triggered release of TM for sustained therapy. We find that ND-embedded lenses composed of enzyme-cleavable polymers allow for controlled and sustained release of TM in the presence of lysozyme. Retention of drug activity is verified in primary human trabecular meshwork cells. These results demonstrate the translational potential of an ND-embedded lens capable of drug sequestration and enzyme activation.

Characterization of membrane materials and membrane coatings for bioreactor units of bioartificial kidneys.

The bioreactor unit of bioartificial kidneys contains porous membranes seeded with renal cells. For clinical applications, it is mandatory that human primary renal proximal tubule cells (HPTCs) form differentiated epithelia on the membranes. Here, we show that HPTCs do not grow and survive on a variety of polymeric membrane materials. This applies also to membranes consisting of polysulfone/polyvinylpyrrolidone (PSF/PVP), which have been used in the bioreactor unit of bioartificial kidneys after coating with an extracellular matrix (ECM). Our data reveal that coating with just an ECM does not sufficiently improve HPTC performance on non-HPTC-compatible membrane materials. On the other hand, we have characterized the effects of a variety of surface treatments and coatings, and found that double coating with 3,4-dihydroxy-l-phenylalanine and an ECM markedly improves HPTC performance and results in the formation of differentiated epithelia on PSF/PVP membranes. We have also synthesized alternative membrane materials, and characterized membranes consisting of polysulfone and Fullcure. We found that these membranes sustain proper HPTC performance without the need for surface treatments or coatings. Together, our data reveal that the materials that have been previously applied in bioartificial kidneys are not suitable for applications with HPTCs. This study elucidates the types of membrane materials and coatings that are favorable for the bioreactor unit of bioartificial kidneys.

Mechanism-Independent Optimization of Combinatorial Nanodiamond and Unmodified Drug Delivery Using a Phenotypically Driven Platform Technology

Combination chemotherapy can mediate drug synergy to improve treatment efficacy against a broad spectrum of cancers. However, conventional multidrug regimens are often additively determined, which have long been believed to enable good cancer-killing efficiency but are insufficient to address the nonlinearity in dosing. Despite improved clinical outcomes by combination treatment, multi-objective combination optimization, which takes into account tumor heterogeneity and balance of efficacy and toxicity, remains challenging given the sheer magnitude of the combinatorial dosing space. To enhance the properties of the therapeutic agents, the field of nanomedicine has realized novel drug delivery platforms that can enhance therapeutic efficacy and safety. However, optimal combination design that incorporates nanomedicine agents still faces the same hurdles as unmodified drug administration. The work reported here applied a powerful phenotypically driven platform, termed feedback system control (FSC), that systematically and rapidly converges upon a combination consisting of three nanodiamond-modified drugs and one unmodified drug that is simultaneously optimized for efficacy against multiple breast cancer cell lines and safety against multiple control cell lines. Specifically, the therapeutic window achieved from an optimally efficacious and safe nanomedicine combination was markedly higher compared to that of an optimized unmodified drug combination and nanodiamond monotherapy or unmodified drug administration. The phenotypically driven foundation of FSC implementation does not require any cellular signaling pathway data and innately accounts for population heterogeneity and nonlinear biological processes. Therefore, FSC is a broadly applicable platform for both nanotechnology-modified and unmodified therapeutic optimizations that represent a promising path toward phenotypic personalized medicine.

Biocompatible pH-responsive nanoparticles with a core-anchored multilayer shell of triblock copolymers for enhanced cancer therapy

Drug nanocarriers are synthesised via a facile self-assembly approach using gold nanoparticles (Au NPs) as a structural core. The nanocarriers feature a multilayer shell of POEGMA-PDPA-PMPC triblock copolymers with a chain-end thiol functional group for anchoring to the Au NP surface. This water-soluble triblock copolymer was synthesised via atom transfer radical polymerisation (ATRP) from a bi-functional initiator containing a disulphide bridge. The resultant nanocarriers exhibit high biocompatibility plus excellent colloidal stability and antifouling capability in bio-media (50% PBS/FBS). Encapsulation and release of a hydrophobic drug can be effectively triggered by a pH-stimulus. Meanwhile drug-loaded nanocarriers show enhanced efficacy towards cancer cells compared to plain drug.

Effects of quantum dots on different renal proximal tubule cell models and on gel-free renal tubules generated in vitro

Abstract We investigated the interactions of different types of human and porcine renal proximal tubule-derived cells with core-shell CdSe@ZnS quantum dots (QDs) coated with polymerized histidine-formaldehyde (pHF). The results revealed that porcine and human proximal tubule cells showed a markedly different uptake behavior. This applied to flat epithelial monolayers, as well as to proximal tubules formed on two-dimensional (2D) surfaces in vitro. Primary human cells were most sensitive to the cytotoxic effects of QDs, but displayed inter-donor variability, which appeared to depend on the state of differentiation. The results suggested that human proximal tubule-derived cells were more appropriate than porcine cells for in vitro nanotoxicology. Primary human cells might be suitable when their state of differentiation and inter-donor variability were well-controlled. Furthermore, the results suggested that gel-free proximal tubules formed in vitro could be used as test system to address uptake and transport of nanometer-sized particles in human renal structures.

Dual-responsive hybrid thermoplastic shape memory polyurethane

A urethane-based dual-responsive shape memory polymer (SMP) comprising poly(ethylene glycol) (PEG), poly(e-caprolactone) (PCL) and poly(dimethylsiloxane) (PDMS) was prepared. Water-responsive SME was achieved through the solvation and recrystallization of PEG switching segments. Thermo-responsive SME of the copolymer at physiological temperature was also demonstrated. The dual-responsive SMP shows promise for biomedical applications in which the physiological environment ensures constant exposure to water for water-triggered actuation with a suitable response time, while the thermally-triggered SME of the copolymer may be utilised to further augment shape recovery.

A new light triggered approach to develop a micro porous tough hydrogel

A porous tough hydrogel (alginate–polyacrylamide) is successfully synthesized using a photo-gelling polymer as a templating agent. Unlike current porous hydrogels, we present a useful pore-enhancing strategy without sacrificing the mechanical properties of the parent matrix. These porous tough hydrogels, as 3D cell culture scaffolds, can mimic the extracellular matrix and allow maximum nutrient exchange.

Electrospun Pectin-Polyhydroxybutyrate Nanofibers for Retinal Tissue Engineering

Natural polysaccharide pectin has for the first time been grafted with polyhydroxybutyrate (PHB) via ring-opening polymerization of β-butyrolactone. This copolymer, pectin-polyhydroxybutyrate (pec-PHB), was blended with PHB in various proportions and electrospun to produce nanofibers that exhibited uniform and bead-free nanostructures, suggesting the miscibility of PHB and pec-PHB. These nanofiber blends exhibited reduced fiber diameters from 499 to 336–426 nm and water contact angles from 123.8 to 88.2° on incorporation of pec-PHB. They also displayed 39–335% enhancement of elongation at break relative to pristine PHB nanofibers. pec-PHB nanofibers were found to be noncytotoxic and biocompatible. Human retinal pigmented epithelium (ARPE-19) cells were seeded onto pristine PHB and pec-PHB nanofibers as scaffold and showed good proliferation. Higher proportions of pec-PHB (pec-PHB10 and pec-PHB20) yielded higher densities of cells with similar characteristics to normal RPE cells. We propose, therefore, that nanofibers of pec-PHB have significant potential as retinal tissue engineering scaffold materials.