Imperial College London

ProfessorRongjunChen

Faculty of EngineeringDepartment of Chemical Engineering

Professor of Biomaterials Engineering
 
 
 
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Contact

 

+44 (0)20 7594 2070rongjun.chen Website

 
 
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Location

 

408ACE ExtensionSouth Kensington Campus

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Summary

 

Publications

Publication Type
Year
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82 results found

Chen S, Morrison G, Liu W, Bhamra A, Chen Ret al., 2022, A pH-responsive, endosomolytic liposome functionalized with membrane-anchoring, comb-like pseudopeptides for enhanced intracellular delivery and cancer treatment, Biomaterials Science, ISSN: 2047-4830

Low intracellular delivery efficiency and multidrug resistance are among major barriers to effective cancer therapy. Herein, we report a novel, virus-mimicking, endosomolytic liposomal drug-delivery platform to address these two key challenges. The pH-responsive, comb-like pseudopeptides were prepared by grafting relatively long alkyl side chains onto a polyamide, poly(L-lysine isophthalamide), to mimic fusogenic peptides in viral spikes. The cholesterol-containing liposome, which mimics the viral envelope, was readily coated with these pseudopeptides due to their hydrophobic side chains acting as membrane anchors. These endosomolytic pseudopeptides displayed high adsorption onto the liposomal membrane and enabled the significantly higher cellular uptake. The virus-mimicking system showed a pH-triggered content-release profile which could be manipulated by varying the structure and concentration of the adsorbed polymers. The endosomolytic ability of the multifunctional liposome and its use for efficient intracellular delivery of the widely used anticancer drug doxorubicin (DOX) were demonstrated. The virus-mimicking liposomal system with DOX encapsulation exhibited considerably higher potency against HeLa cervical cancer cells, A549 lung cancer cells, MES-SA uterus cancer cells, and MES-SA/DX5 multidrug-resistant cancer cells than DOX-loaded bare liposomes and free DOX. These results suggest its potential applications for enhanced cytoplasmic delivery and cancer treatment.

Journal article

Huang Y, Jiang J, Ren J, Guo Y, Zhao Q, Zhou J, Li Y, Chen Ret al., 2022, A fibrinogen-mimicking, activated-platelet-sensitive nanocoacervate enhances thrombus targeting and penetration of tissue plasminogen activator for effective thrombolytic therapy., Advanced Healthcare Materials, Vol: 11, Pages: 1-17, ISSN: 2192-2640

Development of a fibrinolytic system with long circulation time, high thrombus targeting, efficient thrombus penetration, effective thrombolysis and minimal hemorrhagic risk remains a major challenge. Herein, inspired by fibrinogen binding to activated platelets in thrombosis, we report a fibrinogen-mimicking, activated-platelet-sensitive nanocoacervate to enhance thrombus penetration of tissue plasminogen activator (tPA) for targeted thrombolytic therapy. This biomimetic nanothrombolytic system, denoted as RGD-Chi@tPA, was constructed by "one-pot" coacervation through electrostatic interactions between positively charged arginine-glycine-aspartic acid (RGD)-grafted chitosan (RGD-Chi) and negatively charged tPA. Flow cytometry and confocal laser scanning microscopy measurements showed a targeting of RGD-Chi@tPA to activated platelets. Controlled tPA release triggered by activated platelets at a thrombus site was demonstrated. Its targeted fibrinolytic and thrombolytic activities were measured in vitro models. The pharmacokinetic profiles showed that RGD-Chi@tPA could significantly prolong circulation time compared to free tPA. In a mouse tail thrombus model, RGD-Chi@tPA displayed efficient thrombus targeting and penetration, enabling a complete vascular recanalization as confirmed by the fluorescence imaging, histochemical assay and laser speckle contrast imager. Consequently, RGD-Chi@tPA induced a substantial enhancement in thrombolysis with minimal hemorrhagic risk compared to free tPA. This simple, effective and safe platform holds a great promise for development of thrombolytic nanomedicines. This article is protected by copyright. All rights reserved.

Journal article

Zheng X, Pan D, Zhu G, Zhang L, Bhamra A, Chen R, Zhang H, Gong Q, Gu Z, Luo Ket al., 2022, A Dendritic Polymer‐Based Nanosystem Mediates Drug Penetration and Irreversible Endoplasmic Reticulum Stresses in Tumor via Neighboring Effect, Advanced Materials, Vol: 34, Pages: 2201200-2201200, ISSN: 0935-9648

Journal article

Gu L, Duan Z, Chen X, Li X, Luo Q, Bhamra A, Pan D, Zhu H, Tian X, Chen R, Gu Z, Zhang H, Qian Z, Gong Q, Luo Ket al., 2022, A transformable amphiphilic and block polymer-dendron conjugate for enhanced tumor penetration and retention with cellular homeostasis perturbation via membrane flow., Advanced Materials, Vol: 34, Pages: 1-14, ISSN: 0935-9648

Efficient penetration and retention of therapeutic agents in tumor tissues can be realized through rational design of drug delivery systems. Herein, we present a polymer-dendron conjugate, POEGMA-b-p(GFLG-Dendron-Ppa) (GFLG-DP), which allows cathepsin B (CTSB)-triggered stealthy-to-sticky structural transformation. The compositions and ratios were optimized through dissipative particle dynamics simulations. GFLG-DP displayed tumor-specific transformation and consequently released dendron-Ppa was found to effectively accumulate on the tumor cell membrane. The interaction between dendron-Ppa and the tumor cell membrane resulted in intracellular and intercellular transport via membrane flow, thus achieving efficient deep penetration and prolonged retention of therapeutic agents in solid tumor tissues. Meanwhile, the interaction of dendron-Ppa with endoplasmic reticulum disrupted the cell homeostasis, making tumor cells more vulnerable and susceptible to the photodynamic therapy. This platform represents a versatile approach to augmenting the tumor therapeutic efficacy of a nanomedicine via manipulation of its interactions with tumor membrane systems. This article is protected by copyright. All rights reserved.

Journal article

Luo Q, Duan Z, Li X, Gu L, Ren L, Zhu H, Tian X, Chen R, Zhang H, Gong Q, Gu Z, Luo Ket al., 2022, Branched polymer-based redox/enzyme-activatable photodynamic nanoagent to trigger STING-dependent immune responses for enhanced therapeutic effect, Advanced Functional Materials, Vol: 32, Pages: 1-14, ISSN: 1616-301X

Immune response in the tumor microenvironment (TME) is an essential therapeutic factor for antitumor therapy. Herein, to improve immunostimulatory effects, photodynamic therapy (PDT) is combined with AZD2281 to trigger the stimulator of interferon genes (STING)-dependent immune responses. A synthetic branched polymer-pyropheophorbide a (Ppa) conjugate (BGSSP) is designed and developed in response to redox/cathepsin B of the TME. This conjugate with a unique structure and a large molecular weight (MW) can self-assemble into a compact structure via hydrophilic and hydrophobic forces, inducing self-quenching of conjugated Ppa. AZD2281 is encapsulated in BGSSP to obtain a TME-activatable photodynamic nanoagent, AZD@BGSSP. AZD@BGSSP with a stable assembly structure accumulates effectively in tumors and enters lysosomes through endocytosis pathways. Polymer degradation, Ppa activation, and AZD2281 release are achieved after exposure of AZD@BGSSP to highly expressed cathepsin B and glutathione in tumor cells. After laser irradiation, AD2281 inhibits the repair of damaged DNA caused by ROS from PDT and promotes generation of cytosolic DNA, which activates the cGAS-STING pathway and further induces interferons-mediated immune responses and a long-term immune memory effect for immunotherapy. This nanoagent opens a new door to combination PDT and immune response for anti-cancer treatment.

Journal article

Pan D, Zheng X, Zhang L, Li X, Zhu G, Gong M, Kopytynski M, Zhou L, Yi Y, Zhu H, Tian X, Chen R, Zhang H, Gu Z, Gong Q, Luo Ket al., 2022, Synergistic disruption of metabolic homeostasis through hyperbranched poly(ethylene glycol) conjugates as nanotherapeutics to constrain cancer growth, Advanced Materials, Vol: 34, ISSN: 0935-9648

Combination therapy is a promising approach for effective treatment of tumors through synergistically regulating pathways. However, the synergistic effect is limited, likely by uncontrolled co-delivery of different therapeutic payloads in a single nanoparticle. Herein, we developed a combination nanotherapeutic by using two amphiphilic conjugates hyperbranched poly(ethylene glycol)-pyropheophorbide-a (Ppa) (HP-P) and hyperbranched poly(ethylene glycol)-doxorubicin (DOX) (HP-D) to construct co-assembly nanoparticles (HP-PD NPs) for controllably co-loading and co-delivering Ppa and DOX. In vitro and in vivo anti-tumor studies confirmed the synergistic effect of photodynamic therapy and chemotherapy from HP-PD NPs. Metabolic variations revealed that tumor suppression was associated with disruption of metabolic homeostasis, leading to reduced protein translation. Our study uncovers the manipulation of metabolic changes in tumor cells through disruption of cellular homeostasis using HP-PD NPs and provides a new insight into rational design of synergistic nanotherapeutics for combination therapy.

Journal article

Cai H, Tan P, Chen X, Kopytynski M, Pan D, Zheng X, Gu L, Gong Q, Tian X, Gu Z, Zhang H, Chen R, Luo Ket al., 2022, Stimuli-sensitive linear-dendritic block copolymer-drug prodrug as nano-platform for tumor combination therapy., Advanced Materials, Vol: 34, Pages: 1-15, ISSN: 0935-9648

Linear-dendritic block copolymer (LDBCs) are highly attractive candidates for smart drug delivery vehicles. Herein, we report an amphiphilic poly[(ethylene glycol) methyl ether methacrylate] (POEGMA) linear-peptide dendritic prodrug of doxorubicin (DOX) prepared by reversible addition-fragmentation chain transfer (RAFT) polymerization. A hydrophobic dye-based photosensitizer chlorin e6 (Ce6) was employed for encapsulation in the prodrug nanoparticles (NPs) to obtain a LDBCs-based drug delivery system (LD-DOX/Ce6) which offered a combination cancer therapy. Due to the presence of Gly-Phe-Leu-Gly peptides and hydrazone bonds in the prodrug structure, LD-DOX/Ce6 were degraded into small fragments, thus specifically triggering the intracellular release of DOX and Ce6 in the tumor microenvironment. Bioinformatics analysis suggested that LD-DOX/Ce6 with laser irradiation treatment significantly induced apoptosis, DNA damage and cell cycle arrest. The combination treatment could not only suppress tumor growth, but also significantly reduced tumor metastasis compared with treatments with DOX or Ce6 through regulating EMT pathway, TGFβ pathway, angiogenesis and the hypoxia pathway. LD-DOX/Ce6 displayed a synergistic chemo-photodynamic anti-tumor efficacy, resulting in a high inhibition in tumor growth and metastasis, while maintaining an excellent biosafety. Therefore, this study has demonstrated potential of the biodegradable and tumor microenvironment-responsive LDBCs as an intelligent multifunctional drug delivery vehicle for high-efficiency cancer combination therapy. This article is protected by copyright. All rights reserved.

Journal article

Gu B, Huang Y, Manchester E, Hughes A, Thom S, Chen R, Xu XYet al., 2022, Multiphysics modelling and simulation of thrombolysis via activated platelet-targeted nanomedicine, Pharmaceutical Research, Vol: 39, Pages: 41-56, ISSN: 0724-8741

Purpose:This study establishes a multiphysics simulation platform for both conventional and targeted thrombolysis using tissue plasminogen activator (tPA). Based on our computational results, the effects of therapeutic parameters on the dynamics of thrombolysis and the risk of side effects are investigated.Methods:The model extends our previously developed one-dimensional(1D) mathematical models for fibrinolysis by incorporating targeted thrombolysis. It consists of two parts: (i) a coupled mathematical model of systemic pharmacokinetics (PK) and pharmacodynamics (PD) and local PD in a 1D occluded artery, and (ii) a mechanistic model for a targeted thrombolytic system via activated platelet-targeted tPA-loaded nanovesicles (tPA-NV), with model parameters derived from our in vitro experiments. A total of 16 therapeutic scenarios are simulated by varying the clot location and composition as well as the dosing regimen with free tPA or tPA-NV.Results:Our simulation results indicate that tPA-NV offers several advantages over free tPA for thrombolysis. It reduces systemic exposure of tPA, thereby minimising the risk of bleeding complications. Simulations with different tPA-NV doses reveal that tPA-NV at 10% of the recommended dose can be as effective as the standard regimen with the full recommended dose of free tPA, demonstrating the potential of our tPA-NV as a new thrombolytic strategy with a reduced tPA dose. Moreover, faster recanalisation can be achieved with tPA-NV, especially for platelet-rich(or fibrin-poor) clots.Conclusions:Our simulation platform for thrombolysis with well-tuned model parameters can be used to evaluate and optimise treatment regimens of existing and new thrombolytic therapies via benefit/risk assessment under various therapeutic scenarios.

Journal article

Chen R, Bhamra A, Shattock R, Blakney Aet al., 2021, Payload delivery system

Patent

Chen R, Liu X, Shattock R, Blakney Aet al., 2021, Sub-micron particle

Patent

Shmool T, Bhamra A, Chen R, Hallett Jet al., 2021, Stable composition

Patent

Tan P, Cai H, Wei Q, Tang X, Zhang Q, Kopytynski M, Yang J, Yi Y, Zhang H, Gong Q, Gu Z, Chen R, Luo Ket al., 2021, Enhanced chemo-photodynamic therapy of an enzyme-responsive prodrug in bladder cancer patient-derived xenograft models, Biomaterials, Vol: 277, Pages: 1-13, ISSN: 0142-9612

Patient-derived xenograft (PDX) models are powerful tools for understanding cancer biology and drug discovery. In this study, a polymeric nano-sized drug delivery system poly(OEGMA)-PTX@Ce6 (NPs@Ce6) composed of a photosensitizer chlorin e6 (Ce6) and a cathepsin B-sensitive polymer-paclitaxel (PTX) prodrug was constructed. The photochemical internalization (PCI) effect and enhanced chemo-photodynamic therapy (PDT) were achieved via a two-stage light irradiation strategy. The results showed that the NPs@Ce6 had great tumor targeting and rapid cellular uptake induced by PCI, thereby producing excellent anti-tumor effects on human bladder cancer PDX models with tumor growth inhibition greater than 98%. Bioinformatics analysis revealed that the combination of PTX chemotherapy and PDT up-regulated oxidative phosphorylation and ROS generation, blocked cell cycle and proliferation, and down-regulated the pathways related to tumor progression, invasion and metastasis, including hypoxia, TGF-β signaling and TNF-α signaling pathways. Western blots analysis confirmed that proteins promoting apoptosis (Bax, cleaved caspase-3, cleaved PARP) and DNA damage (γH2A.X) were up-regulated, while those inhibiting apoptosis (Bcl-2) and mitosis (pan-actin and α/β-tubulin) were down-regulated after chemo-PDT treatment. Therefore, this stimuli-responsive polymer-PTX prodrug-based nanomedicine with combinational chemotherapy and PDT evaluated in the PDX models could be a potential candidate for bladder cancer therapy.

Journal article

Huang Y, Gu B, Salles II, Taylor KA, Yu L, Ren J, Liu X, Emerson M, Longstaff C, Hughes AD, Thom SA, Xu XY, Chen Ret al., 2021, Fibrinogen-mimicking, multi-arm nanovesicles for human thrombus-specific delivery of tissue plasminogen activator and targeted thrombolytic therapy, Science Advances, Vol: 7, ISSN: 2375-2548

Clinical use of tissue plasminogen activator (tPA) in thrombolytic therapy is limited by its short circulation time and hemorrhagic side effects. Inspired by fibrinogen binding to activated platelets, we report a fibrinogen-mimicking, multi-arm nanovesicle for thrombus-specific tPA delivery and targeted thrombolysis. This novel system is based on the lipid nanovesicle coated with polyethylene glycol (PEG) terminally conjugated with a cyclic RGD (cRGD) peptide. Our experiments with human blood demonstrated its highly selective binding to activated platelets and efficient tPA release at a thrombus site under both static and physiological flow conditions. Its clot dissolution time in a microfluidic system was comparable to that of free tPA. Furthermore, we report a purpose-built computational model capable of simulating targeted thrombolysis of the tPA-loaded nanovesicle and with potential in predicting the dynamics of thrombolysis in physiologically realistic scenarios. This combined experimental and computational work presents a promising platform for development of thrombolytic nanomedicines.

Journal article

Huang Y, Wang Z, Zhang G, Ren J, Yu L, Liu X, Yang Y, Ravindran A, Wong C, Chen Ret al., 2021, A pH/redox-dual responsive, nanoemulsion-embedded hydrogel for efficient oral delivery and controlled intestinal release of magnesium ions, Journal of Materials Chemistry B, Vol: 9, Pages: 1888-1895, ISSN: 2050-750X

It remains a major challenge to achieve efficient oral delivery and controlled intestinal release of ions using hydrogels. Herein, we report a novel, pH/redox-dual responsive, nanoemulsion-embedded composite hydrogel to address this issue. The hydrogel was first synthesized by crosslinking a biocompatible, pH-responsive pseudopeptide, poly(L-lysine isophthalamide) (PLP), and redox-sensitive L-cystine dimethyl ester dihydrochloride (CDE). A suitable amount of magnesium acetate was encapsulated into oil-in-water nanoemulsions, which were then embedded into the lysine-based hydrogel. The resulting composite hydrogel collapsed into a compact structure at acidic gastric pH, but became highly swollen or degraded in the neutral and reducing intestinal environment. The ion release profiles indicated that the nanoemulsion-embedded composite hydrogel could well retain and protect magnesium ions in the simulated gastric fluid (SGF) buffer at pH 1.2, but efficiently release them in the simulated intestinal fluid (SIF) buffer at pH 6.8 in the presence of 1,4-dithiothreitol (DTT) as a reducing agent. Moreover, this composite hydrogel system displayed good biocompatibility. These results suggested that the pH/redox-dual responsive, nanoemulsion-embedded composite hydrogel could be a promising candidate for efficient oral delivery and controlled intestinal release of magnesium and other ions.

Journal article

Li Y, Tan T, Zhao Y, Wei Y, Wang D, Chen R, Tao Let al., 2020, Anticancer polymers via the biginelli reaction, ACS Macro Letters, Vol: 9, Pages: 1249-1254, ISSN: 2161-1653

We developed a polymer–drug strategy to explore anticancer polymers. A series of monomers containing groups with potential anticancer activity have been facilely prepared through the Biginelli reaction. These monomers were used to produce water-soluble polymers through convenient radical copolymerization. The resulting polymers are biocompatible and can be directly used to suppress proliferation of different cancer cells without the release of small molecules. Theoretical calculations revealed that Biginelli groups in polymers had strong interaction with the Eg5 protein, which is highly expressed in cancer cells and is closely related to cell mitosis. Subsequent cell experiments confirmed that a screened polymer is efficient in inhibiting mitosis in different cancer cells. Our study of exploring functional polymers via the combination of multicomponent reactions and theoretical calculation resulted in promising anticancer polymers, which might pave a path for de novo designing of functional polymers and have important implications in the fields of organic, computational, and polymer chemistry.

Journal article

Chen R, Yu L, Tang Y, 2020, Polymer

Patent

Chen R, Huang Y, Xu XY, Thom Set al., 2020, Red Blood Cell-Derived Vesicle

Patent

Chen S, Wu L, Ren J, Bemmer VL, Zajicek R, Chen Ret al., 2020, Comb-like pseudopeptides enable very rapid and efficient intracellular trehalose delivery for enhanced cryopreservation of erythrocytes, ACS Applied Materials & Interfaces, Vol: 12, Pages: 28941-28951, ISSN: 1944-8244

Cell cryopreservation plays a key role in development of reproducible and cost-effective cell-based therapies. Trehalose accumulated in freezing and desiccation tolerant organisms in nature has been sought as an attractive non-toxic cryoprotectant. Herein, we report a co-incubation method for very rapid and efficient delivery of membrane-impermeable trehalose into ovine erythrocytes through reversible membrane permeabilization using pH-responsive, comb-like pseudopeptides. The pseudopeptidic polymers containing relatively long alkyl side chains were synthesized to mimic membrane-anchoring fusogenic proteins. The intracellular trehalose delivery efficiency was optimized by manipulating the side chain length, degree of substitution and concentration of the pseudopeptides with different hydrophobic alkyl side chains, the pH, temperature and time of incubation, as well as the polymer-to-cell ratio and the concentration of extracellular trehalose. Treatment of erythrocytes with the comb-like pseudopeptides for only 15 min yielded an intracellular trehalose concentration of 177.9 ± 8.6 mM, which resulted in 90.3 ± 0.7% survival after freeze-thaw. The very rapid and efficient delivery was found to be attributed to the reversible, pronounced membrane curvature change as a result of strong membrane insertion of the comb-like pseudopeptides. The pseudopeptides can enable efficient intracellular delivery of not only trehalose for improved cell cryopreservation, but also other membrane-impermeable cargos.

Journal article

Tascini AS, Wang S, Seddon JM, Bresme F, Chen Ret al., 2020, Fats’ love–hate relationships: a molecular dynamics simulation and hands-on experiment outreach activity to introduce the amphiphilic nature and biological functions of lipids to young students and the general public, Journal of Chemical Education, Vol: 97, Pages: 1360-1367, ISSN: 0021-9584

Lipids are fundamental components of biological organisms and have important applications in the pharmaceutical, food, and cosmetics industries. Thus, it is important that young students and the general public properly understand the basic properties of lipids and how these relate to their biological and industrial roles. Here, we use molecular dynamics computer simulations and a simple, safe, and inexpensive popular hands-on activity, to communicate to participants why and how lipid molecules play a fundamental role in all living organisms and in our bodies. The activity is called “Fats’ Love–Hate Relationships”, to highlight how the different parts of amphiphilic lipids interact with water. This “love–hate relationship” is vital to the biological functions of lipids and drives the formation of lipid structures that can be visualized at molecular scale with the computer simulations. The participants were encouraged to investigate the interactions between milk lipids and soap surfactants, creating beautiful complex artwork that they could then take home. The hands-on activity was accompanied by a video of a molecular simulation that illustrates milk–soap interactions at a molecular scale and helps to explain how the amphiphilicity of lipids creates the beautiful artwork at a molecular level. The outreach activity has been performed in science festivals and in classrooms and has been well received by participants of all ages with multiple learner comprehension levels (primary and secondary school students and the general public). By combining molecular simulation, explanations of the amphiphilic structure of the lipids, and an engaging hands-on activity, we explained how lipids interact with water and surfactants and inspired discussions on the link between the structure of the lipids and their biological function, namely, their structural and protective roles as a key component of cell membranes.

Journal article

Huang Y, Qiu F, Chen R, Yan D, Zhu Xet al., 2020, Fluorescence resonance energy transfer-based drug delivery systems for enhanced photodynamic therapy, Journal of Materials Chemistry B, Vol: 8, Pages: 3772-3788, ISSN: 2050-750X

Photodynamic therapy (PDT) has received an increasing attention in disease treatment due to its minimally-invasive, selective destruction with combination of a photosensitizer (PS), light, and oxygen. However, the limited cytotoxic singlet oxygen (1O2) generation and thin tissue penetrability have been two major barriers in the conventional PDT, hindering its further development and clinical use. Recently, fluorescence resonance energy transfer-based drug delivery systems (FRET-DDSs), indirectly activating PS drugs by a donor fluorophore, have been successfully applied to alleviate these issues. The transfer of excitation energy from donors to PS drugs can significantly boost its light harvesting and extend the field of light source, which dramatically improves its production efficiency of singlet oxygen, thus leading to highly efficient and deep-tissue-penetrable PDT for the treatment of bacteria, cancer and other diseases. In this Review, we give the first-known overview of recent advances in FRET-DDSs for the enhanced PDT. In particular, dependent on the excitation energy mechanism in the FRET process, six major types of FRET-DDSs, including one-photon, two-photon, upconversion, auto-fluorescence, X-ray, and Cerenkov excited FRET-DDSs in PDT applications are summarized in detail. Furthermore, future research directions and perspectives in this emerging field are also discussed.

Journal article

Li L, Xiao B, Mu J, Zhang Y, Zhang C, Cao H, Chen R, Patra HK, Yang B, Feng S, Tabata Y, Slater NKH, Tang J, Shen Y, Gao Jet al., 2019, A MnO2 nanoparticle-dotted hydrogel promotes spinal cord repair via regulating reactive oxygen species microenvironment and synergizing with mesenchymal stem cells, ACS Nano, Vol: 13, Pages: 14283-14293, ISSN: 1936-0851

Spinal cord injury (SCI) is one of the most debilitating injuries and transplantation of stem cells in a scaffold is a promising strategy for the treatment. However, the stem cell treatment of SCI has been severely impaired by the increased generation of reactive oxygen species in the lesion microenvironment, which can lead to a high level of stem cell death and dysfunction. Herein, a MnO2 nanoparticle (NP)-dotted hydrogel is prepared through dispersion of MnO2 NPs in a PPFLMLLKGSTR peptide modified hyaluronic acid hydrogel. The peptide modified hydrogel enables the adhesive growth of mesenchymal stem cells (MSCs) and nerve tissue bridging. The MnO2 NPs alleviate the oxidative environment, thereby effectively improving the viability of MSCs. Transplantation of MSCs in the multifunctional gel generates a significant motor function restoration on a long-span rat spinal cord transection model and induces an in vivo integration as well as neural differentiation of the implanted MSCs, leading to a highly efficient regeneration of central nervous spinal cord tissue. Therefore, the MnO2 NP-dotted hydrogel represents a promising strategy for stem cell-based therapies of central nervous system diseases through the comprehensive regulation of pathological microenvironment complications.

Journal article

Kopytynski M, Chen S, Legg S, Minter R, Chen Ret al., 2019, A versatile polymer‐based platform for intracellular delivery of macromolecules, Advanced Therapeutics, Vol: 3, Pages: 1-10, ISSN: 2366-3987

The plasma membrane barrier greatly restricts intracellular delivery of macromolecules. Currently available methods suffer from various limitations, including low delivery efficiency, high cytotoxicity or incompatibility with a wider range of macromolecules or cell types. To overcome these issues, stimuli-responsive polymers such as the bio-inspired, pH-responsive poly(L-lysine isophthalamide) grafted with L-phenylalanine at a stoichiometric ratio of 50% (PP50) can be used. In mildly acidic environments, the pseudopeptidic polymer can permeabilize the plasma membrane overcoming the problem of payload entrapment in the endosomes and allowing for efficient intracellular delivery. We demonstrate that PP50 was capable of intracellular delivery by simple co-incubation at pH 6.5 with various macromolecules, including different-sized Dextrans, green fluorescent protein (GFP) and an apoptotic peptide. The delivery process was fast, non-toxic and compatible with multiple cell types, including adherent and suspension cell lines, primary human mesenchymal stem cells, and cells grown as spheroids. In addition, apoptotic peptide delivery by co-incubation with PP50 was over 3 times more effective than delivery using other common methods, including poly(ethyleneimine) (PEI), cell penetrating peptides (CPPs) and electroporation. Our findings suggest that payload delivery by co-incubation with PP50 is a flexible, controllable method allowing delivery of various payloads to many different cell types in vitro.

Journal article

Gu B, Piebalgs A, Huang Y, Roi D, Lobotesis K, Longstaff C, Hughes AD, Chen R, Thom SA, Xu XYet al., 2019, Computational simulations of thrombolysis in acute stroke: Effect of clot size and location on recanalisation, Medical Engineering & Physics, Vol: 73, Pages: 9-17, ISSN: 1350-4533

Acute ischaemic stroke can be treated by intravenous thrombolysis whereby tissue plasminogen activator (tPA) is infused to dissolve clots that block blood supply to the brain. In this study, we aim to examine the influence of clot location and size on lysis pattern and recanalisation by using a recently developed computational modelling framework for thrombolysis under physiological flow conditions. An image-based patient-specific model is reconstructed which consists of the internal carotid bifurcation with the A1 segment of anterior cerebral arteries and M1 segment of middle cerebral arteries, and the M1 bifurcation containing the M2 segments. By varying the clot size and location, 7 scenarios are simulated mimicking thrombolysis of M1 and M2 occlusions. Our results show that initial breakthrough always occurs along the inner curvature of the occluded cerebral artery, due to prolonged tPA residence time in the recirculation zone. For a given occlusion site, lysis completion time appears to increase almost quadratically with the initial clot volume; whereas for a given clot volume, the simulated M2 occlusions take up to 30% longer for complete lysis compared to the corresponding M1 occlusions.

Journal article

Chen S, Ren J, Chen R, 2019, Cryopreservation and Desiccation Preservation of Cells, Comprehensive Biotechnology, Editors: Moo-Young, Elsevier: Pergamon, Publisher: Pergamon, Pages: 157-166, ISBN: 9780444640468

Cell preservation technology is required to retain cell viability and functionality during storage. It is of critical importance for the development of biobanks and the delivery of emerging cell-based therapies including blood transfusion, immunotherapy, reparative and regenerative medicine, and fertility preservation. Cryopreservation at ultralow temperature is currently the main way of long-term cell storage. Preservation of cells in dried state at room temperature is an attractive strategy to overcome the limitations of refrigeration and enable easy transportation. Although achievements have been made in preservation of human, animal and bacteria cells, there is still much space for improving their survival rate and functionality. Cell injuries may easily occur during freezing and drying steps, especially for mammalian cells which are more delicate and freezing/desiccation sensitive. This article reviews the mechanisms of cell damage, describes the challenges for cell preservation, and presents the technologies and protectants used in this rapidly growing field.

Book chapter

Huang Y, Yu L, Ren J, Gu B, Longstaff C, Hughes AD, Thom SA, Xu XY, Chen Ret al., 2019, An activated-platelet-sensitive nanocarrier enables targeted delivery of tissue plasminogen activator for effective thrombolytic therapy, Journal of Controlled Release, Vol: 300, Pages: 1-12, ISSN: 0168-3659

It remains a major challenge to develop a selective and effective fibrinolytic system for thrombolysis with minimal undesirable side effects. Herein, we report a multifunctional liposomal system (164.6 ± 5.3 nm in diameter) which can address this challenge through targeted delivery and controlled release of tissue plasminogen activator (tPA) at the thrombus site. The tPA-loaded liposomes were PEGylated to improve their stability, and surface coated with a conformationally-constrained, cyclic arginine-glycine-aspartic acid (cRGD) to enable highly selective binding to activated platelets. The in vitro drug release profiles at 37 °C showed that over 90% of tPA was released through liposomal membrane destabilization involving membrane fusion upon incubation with activated platelets within 1 h, whereas passive release of the encapsulated tPA in pH 7.4 PBS buffer was 10% after 6 h. The release of tPA could be readily manipulated by changing the concentration of activated platelets. The presence of activated platelets enabled the tPA-loaded, cRGD-coated, PEGylated liposomes to induce efficient fibrin clot lysis in a fibrin-agar plate model and the encapsulated tPA retained 97.4 ± 1.7% of fibrinolytic activity as compared with that of native tPA. Furthermore, almost complete blood clot lysis was achieved in 75 min, showing considerably higher and quicker thrombolytic activity compared to the tPA-loaded liposomes without cRGD labelling. These results suggest that the nano-sized, activated-platelet-sensitive, multifunctional liposomes could facilitate selective delivery and effective release of tPA at the site of thrombus, thus achieving efficient clot dissolution whilst minimising undesirable side effects.

Journal article

He M, Huang L, Hou X, Zhong C, Bachir ZA, Lan M, Chen R, Gao Fet al., 2019, Efficient ovalbumin delivery using a novel multifunctional micellar platform for targeted melanoma immunotherapy, International Journal of Pharmaceutics, Vol: 560, Pages: 1-10, ISSN: 0378-5173

Cancer immunotherapy is considered to be one of the alternatives to traditional chemotherapy. It's known that foreign antigen, such as ovalbumin (OVA), can label tumor cells, leading to neoantigen recognition by cytotoxic T lymphocytes. Herein, a novel multifunctional micelle coated with PEGylated hyaluronic acid (HA) was prepared through self-assembly and electrostatic interaction. The OVA-loaded micelle with uniform size (132.1 ± 0.2 nm in diameter) exhibited favorable stability and sustained release profiles. The HA-coated micelle could target CD44-overexpressed cells and enhance the cellular uptake of OVA by 11.9 fold compared to free OVA. In vitro studies revealed that the cationic polymer, polyethyleneimine, could facilitate endosomal escape of OVA to label a tumor cell. After treatment with the OVA-loaded micelle, tumor growth in mice was significantly inhibited by 70% compared to the group treated with free OVA. All these results suggest the potential application of the immunotherapeutic micellar platform for melanoma treatment.

Journal article

Gu B, Piebalgs A, Huang Y, Longstaff C, Hughes A, Chen R, Thom S, Xu Xet al., 2019, Mathematical modelling of intravenous thrombolysis in acute ischaemic stroke: Effects of dose regimens on levels of fibrinolytic proteins and clot lysis time, Pharmaceutics, Vol: 11, ISSN: 1999-4923

Thrombolytic therapy is one of the medical procedures in the treatment of acute ischaemic stroke (AIS), whereby the tissue plasminogen activator (tPA) is intravenously administered to dissolve the obstructive blood clot. The treatment of AIS by thrombolysis can sometimes be ineffective and it can cause serious complications, such as intracranial haemorrhage (ICH). In this study, we propose an efficient mathematical modelling approach that can be used to evaluate the therapeutic efficacy and safety of thrombolysis in various clinically relevant scenarios. Our model combines the pharmacokinetics and pharmacodynamics of tPA with local clot lysis dynamics. By varying the drug dose, bolus-infusion delay time, and bolus-infusion ratio, with the FDA approved dosing protocol serving as a reference, we have used the model to simulate 13 dose regimens. Simulation results are compared for temporal concentrations of fibrinolytic proteins in plasma and the time that is taken to achieve recanalisation. Our results show that high infusion rates can cause the rapid degradation of plasma fibrinogen, indicative of increased risk for ICH, but they do not necessarily lead to fast recanalisation. In addition, a bolus-infusion delay results in an immediate drop in plasma tPA concentration, which prolongs the time to achieve recanalisation. Therefore, an optimal administration regimen should be sought by keeping the tPA level sufficiently high throughout the treatment and maximising the lysis rate while also limiting the degradation of fibrinogen in systemic plasma. This can be achieved through model-based optimisation in the future.

Journal article

Dong R, Liu R, Gaffney PRJ, Schaepertoens M, Marchetti P, Williams CM, Chen R, Livingston AGet al., 2019, Author Correction: Sequence-defined multifunctional polyethers via liquid-phase synthesis with molecular sieving, Nature Chemistry, Vol: 11, Pages: 184-184, ISSN: 1755-4330

Correction to: Nature Chemistry https://doi.org/10.1038/s41557-018-0169-6, published online 3 December 2018.

Journal article

Dong R, Liu R, Gaffney P, Schaepertoens M, Marchetti P, Williams C, Chen R, Livingston Aet al., 2019, Sequence-defined multifunctional polyethers via liquid-phase synthesis with molecular sieving, Nature Chemistry, Vol: 11, Pages: 136-145, ISSN: 1755-4330

Synthetic chemists have devoted tremendous effort towards the production of precision synthetic polymers with defined sequences and specific functions. However, the creation of a general technology that enables precise control over monomer sequence, with efficient isolation of the target polymers, is highly challenging. Here, we report a robust strategy for the production of sequence-defined synthetic polymers through a combination of liquid-phase synthesis and selective molecular sieving. The polymer is assembled in solution with real-time monitoring to ensure couplings proceed to completion, on a three-armed star-shaped macromolecule to maximize efficiency during the molecular sieving process. This approach is applied to the construction of sequence-defined polyethers, with side-arms at precisely defined locations that can undergo site-selective modification after polymerization. Using this versatile strategy, we have introduced structural and functional diversity into sequence-defined polyethers, unlocking their potential for real-life applications in nanotechnology, healthcare and information storage.

Journal article

Tascini AS, Noro MG, Seddon JM, Chen R, Bresme Fet al., 2019, Mechanisms of lipid extraction from skin lipid bilayers by sebum triglycerides, Physical Chemistry Chemical Physics, Vol: 21, Pages: 1471-1477, ISSN: 1463-9076

The skin surface, our first barrier against the external environment, is covered by the sebum oil, a lipid film composed of sebaceous and epidermal lipids, which is important in the regulation of the hydration level of our skin. Here, we investigate the pathways leading to the transfer of epidermal lipids from the skin lipid bilayer to the sebum. We show that the sebum triglycerides, a major component of sebum, interact strongly with the epidermal lipids and extract them from the bilayer. Using microsecond time scale molecular dynamics simulations, we identify and quantify the free energy associated with the skin lipid extraction process.

Journal article

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