Xiaoyuan Wang

Programmable Nano–Bio Interfaces for Functional Biointegrated Devices

A large amount of evidence has demonstrated the revolutionary role of nanosystems in the screening and shielding of biological systems. The explosive development of interfacing bioentities with programmable nanomaterials has conveyed the intriguing concept of nano-bio interfaces. Here, recent advances in functional biointegrated devices through the precise programming of nano-bio interactions are outlined, especially with regard to the rational assembly of constituent nanomaterials on multiple dimension scales (e.g., nanoparticles, nanowires, layered nanomaterials, and 3D-architectured nanomaterials), in order to leverage their respective intrinsic merits for different functions. Emerging nanotechnological strategies at nano-bio interfaces are also highlighted, such as multimodal diagnosis or theragnostics, synergistic and sequential therapeutics delivery, and stretchable and flexible nanoelectronic devices, and their implementation into a broad range of biointegrated devices (e.g., implantable, minimally invasive, and wearable devices). When utilized as functional modules of biointegrated devices, these programmable nano-bio interfaces will open up a new chapter for precision nanomedicine.

“Y”-shape armed amphiphilic star-like copolymers: design, synthesis and dual-responsive unimolecular micelle formation for controlled drug delivery

In this study, a novel amphiphilic star-like CD-PCL-SS-PEG(PNIPAM) copolymer with a disulfide linkage at the junction points of the “Y”-shaped arms is designed and further fabricated into dual temperature and redox-responsive unimolecular micelles for controlled drug delivery in cancer therapy. During the synthesis, the end-alkyne functionalized hydrophobic star-like core CD-PCL-SS-alkyne was first synthesized by ring-opening polymerization (ROP) of e-CL using β-CD as an initiator, followed by a two-step end group transformation reaction. Then, CD-PCL-SS-alkyne was coupled with α,α′-azide, hydroxyl-PEG (PEG-N3(OH)) via “click” chemistry to obtain PCL-SS-(OH)PEG copolymers with reactive –OH at the junction point. Furthermore, esterification between the –OH on PCL-SS-(OH)PEG and S-1-dodecyl-S′-(α,α′-dimethyl-α′′-acetic acid)trithiocarbonate (DDAT) was carried out to afford the CD-PCL-b-(CTA)PEG copolymer, followed by reversible addition–fragmentation chain-transfer polymerization (RAFT) of N-isopropylacrylamide to obtain the desired star-like CD-PCL-SS-PEG(PNIPAM) copolymer. The targeted copolymer and its intermediates were characterized by 1H NMR and gel permeation chromatography (GPC). The unimolecular micelles formed from the CD-PCL-SS-PEG(PNIPAM) copolymer were studied by dynamic light scattering (DLS) and transmission electron microscopy (TEM) techniques. Drug release studies from CD-PCL-SS-PEG(PNIPAM) micelles exhibited sustained release profiles and the rate of release can be tuned by variation of temperature and glutathione (GSH). Cellular uptake and in vitro stimuli-mediated intracellular DOX release were investigated by flow cytometry and confocal laser scanning microscopy (CLSM) measurements, demonstrating high cellular uptake efficiency and significant intracellular drug release from doxorubicin (DOX) loaded CD-PCL-SS-PEG(PNIPAM) micelles via controlling temperature and reduction. Together with the excellent cell biocompatibility, the new star-like CD-PCL-SS-PEG(PNIPAM) copolymer reported in this paper could potentially be used as intelligent nanocarriers for controlled drug delivery.

Codelivery for Paclitaxel and Bcl‐2 Conversion Gene by PHB‐PDMAEMA Amphiphilic Cationic Copolymer for Effective Drug Resistant Cancer Therapy

Antiapoptotic Bcl-2 proteins upregulated expression is a key reason for drug resistance leading to failure of chemotherapy. In this report, a series of biocompatible amphiphilic cationic poly[(R)-3-hydroxybutyrate] (PHB)-b-poly(2-(dimethylamino)ethyl methacrylate) (PDMAEMA) copolymer, comprising hydrophobic PHB block and cationic PDMAEMA block, is designed to codeliver hydrophobic chemotherapeutic paclitaxel and Bcl-2 converting gene Nur77/ΔDBD with enhanced stability, due to the micelle formation by hydrophobic PHB segment. This copolymer shows less toxicity but similar gene transfection efficiency to polyethyenimine (25k). More importantly, this codelivery approach by PHB-PDMAEMA leads to increased drug resistant HepG2/Bcl-2 cancer cell death, by increased expression of Nur77 proteins in the Bcl-2 present intracellular mitochondria. This work signifies for the first time that cationic amphiphilic PHB-b-PDMAEMA copolymers can be utilized for the drug and gene codelivery to drug resistant cancer cells with high expression of antiapoptosis Bcl-2 protein and the positive results are encouraging for the further design of codelivery platforms for combating drug resistant cancer cells.

Overcoming STC2 mediated drug resistance through drug and gene co-delivery by PHB-PDMAEMA cationic polyester in liver cancer cells

Stanniocalcin 2 (STC2) overexpression in hepatocellular carcinoma (HCC) could lead to poor prognosis, which might be due to its induced P-glycoprotein and Bcl-2 protein expression level increase. P-glycoprotein or membrane pump induced drug efflux and altered prosurvival Bcl-2 expression are key mechanisms for drug resistance leading to failure of chemotherapy in HCC. However, current strategy to overcome both P-glycoprotein and Bcl-2 protein induced drug resistance was rarely reported. In this work, we utilized an amphiphilic poly[(R)-3-hydroxybutyrate] (PHB)-b-poly(2-(dimethylamino)ethyl methacrylate) (PDMAEMA) cationic polyester to encapsulate chemotherapeutic paclitaxel (PTX) in hydrophobic PHB domain and Bcl-2 convertor Nur77/ΔDBD gene (Nur77 without DNA binding domain for mitochondria localization) by formation of polyplex due to cationic PDMAEMA segment, to effectively inhibit the drug resistant HepG2/STC2 and SMCC7721/STC2 liver cancer cell growth. Thanks to the cationic nanoparticle complex formation ability and high transfection efficiency to express Bcl-2 conversion proteins, PHB-PDMAEMA/PTX@polyplex could partially impair P-glycoprotein induced PTX efflux and activate the apoptotic function of previous prosurvival Bcl-2 protein. This is the pioneer report of cationic amphiphilic polyester PHB-PDMAEMA to codeliver anticancer drug and therapeutic plasmid to overcome both pump and non-pump mediated chemotherapeutic resistance in liver cancer cells, which might be inspiring for the application of polyester in personalized cancer therapy.

Hierarchically Self-Assembled Supramolecular Host–Guest Delivery System for Drug Resistant Cancer Therapy

In this report, a new star-like copolymer β-CD- g-(PNIPAAm- b-POEGA) x, consisting of a β-CD core, grafted with temperature-responsive poly( N-isopropylacrylamide) (PNIPAAm) and biocompatible poly(oligo(ethylene glycol) acrylate) (POEGA) in a block copolymer of the arms, was used to deliver chemotherapeutics to drug resistant cancer cells and tumors. The first step of the self-assembly process involves the encapsulation of chemotherapeutics through host-guest inclusion complexation between the β-cyclodextrin cavity and the anticancer drug. Next, the chain interaction of the PNIPAAm segment at elevated temperature drives the drug-loaded β-CD- g-(PNIPAAm- b-POEGA) x/PTX inclusion complex to hierarchically self-assemble into nanosized supramolecular assemblies at 37 °C, whereas the presence of poly(ethylene glycol) (PEG) chains in the distal end of the star-like copolymer arms impart enhanced stability to the self-assembled structure. More interestingly, this supramolecular host-guest nanocomplex promoted the enhanced cellular uptake of chemotherapeutics in MDR-1 up-regulated drug resistant cancer cells and exhibited high therapeutic efficacy for suppressing drug resistant tumor growth in an in vivo mouse model, due to the increased stability, improvement in aqueous solubility, enhanced cellular uptake, and partial membrane pump impairment by taking the advantage of PEGylation and supramolecular complex between this star-like copolymer and chemotherapeutics. This work signifies that temperature-sensitive PEGylated supramolecular nanocarriers with good biocompatibility are effective in combating MDR-1 mediated drug resistance in both in vitro and in vivo models, which is of significant importance for the advanced drug delivery platform designed to combat drug resistant cancer.

Thermoresponsive Supramolecular Chemotherapy by “V”‐Shaped Armed β‐Cyclodextrin Star Polymer to Overcome Drug Resistance

Pump mediated drug efflux is the key reason to result in the failure of chemotherapy. Herein, a novel star polymer β-CD-v-(PEG-β-PNIPAAm)7 consisting of a β-CD core, grafted with thermo-responsive poly(N-isopropylacrylamide) (PNIPAAm) and biocompatible poly(ethylene glycol) (PEG) in the multiple V-shaped arms is designed and further fabricated into supramolecular nanocarriers for drug resistant cancer therapy. The star polymer could encapsulate chemotherapeutics between β-cyclodextrin and anti-cancer drug via inclusion complex (IC). Furthermore, the temperature induced chain association of PNIPAAm segments facilitated the IC to form supramolecular nanoparticles at 37 °C, whereas the presence of PEG impart great stability to the self-assemblies. When incubated with MDR-1 membrane pump regulated drug resistant tumor cells, much higher and faster cellular uptake of the supramolecular nanoparticles were detected, and the enhanced intracellular retention of drugs could lead to significant inhibition of cell growth. Further in vivo evaluation showed high therapeutic efficacy in suppressing drug resistant tumor growth without a significant impact on the normal functions of main organs. This work signifies thermo-responsive supramolecular chemotherapy is promising in combating pump mediated drug resistance in both in vitro and in vivo models, which may be encouraging for the advanced drug delivery platform design to overcome drug resistant cancer.

Biomechano‐Interactive Materials and Interfaces

The reciprocal mechanical interaction of engineered materials with biointerfaces have long been observed and exploited in biomedical applications. It contributes to the rise of biomechano-responsive materials and biomechano-stimulatory materials, constituting the biomechano-interactive interfaces. Here, endogenous and exogenous biomechanical stimuli available for mechanoresponsive interfaces are briefed and their mechanistic responses, including deformation and volume change, mechanomanipulation of physical and chemical bonds, dissociation of assemblies, and coupling with thermoresponsiveness are summarized. The mechanostimulatory materials, however, are capable of delivering mechanical cues, including stiffness, viscoelasticity, geometrical constraints, and mechanical loads, to modulate physiological and pathological behaviors of living tissues through the adaptive cellular mechanotransduction. The biomechano-interactive materials and interfaces are widely implemented in such fields as mechanotriggered therapeutics and diagnosis, adaptive biophysical sensors, biointegrated soft actuators, and mechanorobust tissue engineering, which have offered unprecedented opportunities for precision and personalized medicine. Pending challenges are also addressed to shed a light on future advances with respect to translational implementations.

Cyclodextrin-Based Star-Like Amphiphilic Cationic Polymer as a Potential Pharmaceutical Carrier in Macrophages.

Effective delivery of therapeutic genes or small molecular drugs into macrophages is important for cell based immune therapy, but it remains a challenge due to the intracellular reactive oxygen species and endosomal degradation of therapeutics inside immune cells. In this report, the star-like amphiphilic biocompatible β-cyclodextrin-graft-(poly(ε-caprolactone)-block-poly(2-(dimethylamino) ethyl methacrylate)x (β-CD-g-(PCL-b-PDMAEMA)x ) copolymer, consisting of a biocompatible cyclodextrin core, hydrophobic poly(ε-caprolactone) PCL segments and hydrophilic PDMAEMA blocks with positive charge, is optimized to achieve high efficiency gene transfection with enhanced stability, due to the micelle formation by hydrophobic PCL segments. In comparison with lipofetamine, a currently popular nonviral gene carrier, β-CD-g-(PCL-b-PDMAEMA)x copolymer, shows better transfection efficiency of plasmid desoxyribose nucleic acid in RAW264.7 macrophages. More interestingly, this delivery platform by β-CD-g-(PCL-b-PDMAEMA)x not only shows low toxicity but also better dexamethasone delivery efficiency, which might indicate its great potential in immunotherapy.

Thermogelling 3D Systems towards Stem Cell-Based Tissue Regeneration Therapies

Stem cell culturing and differentiation is a very important research direction for tissue engineering. Thermogels are well suited for encapsulating cells because of their non-biotoxic nature and mild sol-gel transition as temperature increases. In particular, thermogels provide a 3D growth environment for stem cell growth, which is more similar to the extracellular matrix than flat substrates, so thermogels as a medium can overcome many of the cell abnormalities caused by 2D cell growth. In this review, we summarize the applications of thermogels in cell and stem cell culture in recent years. We also elaborate on the methods to induce stem cell differentiation by using thermogel-based 3D scaffolds. In particular, thermogels, encapsulating specific differentiation-inducing factor and having specific structures and moduli, can induce the differentiation into the desired tissue cells. Three dimensional thermogel scaffolds that control the growth and differentiation of cells will undoubtedly have a bright future in regenerative medicine.

Hydrogels as Emerging Materials for Translational Biomedicine

Hydrogels have been extensively investigated as biomaterials because of their excellent biocompatibility, and recent developments such as 3D printing and the incorporation of dynamic crosslinks have advanced the field considerably. However, the next step of in vivo translational biomedicine requires an understanding of essential hydrogel properties so that they can be designed to overcome the challenges of the living environment. In this review, the stringent design criteria required for in vivo applications are highlighted and recent advances in the repair of organ tissues (heart, bone, eye, etc.) and the therapeutic delivery of bioactive molecules are described. Commercially available hydrogel systems that can be used for translational biomedicine are also discussed, as is the long and sometimes fraught journey from the laboratory to the clinic.