Imperial College London

DrRongjunChen

Faculty of EngineeringDepartment of Chemical Engineering

Reader in 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
to

66 results found

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

Patent

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

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

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

Wang S, Attah R, Li J, Chen Y, Chen Ret al., 2018, A pH-responsive amphiphilic hydrogel based on pseudopeptides and poly(ethylene glycol) for oral delivery of hydrophobic drugs, ACS Biomaterials Science and Engineering, Vol: 4, Pages: 4236-4243, ISSN: 2373-9878

Oral administration is a noninvasive and convenient drug delivery route most preferred by patients. However, poor stability in the gastrointestinal tract and low bioavailability of hydrophobic drugs has greatly limited their oral administration. To address this problem, we report a pH-responsive, amphiphilic hydrogel drug carrier based on a pseudopeptide poly(l-lysine isophthalamide) (PLP) and poly(ethylene glycol) (PEG). The hydrogels were prepared by a simple N-(3-(dimethylamino)propyl)-N′-ethyl carbodiimide hydrochloride (EDC)/N-hydroxysuccinimide (NHS) coupling reaction, and the cross-linking was confirmed by infrared spectroscopy and differential scanning calorimetry analyses. Because of the pH-responsive conformational alteration of PLP, the hydrogels were relatively hydrophobic and collapsed at acidic pH, but became hydrophilic and swollen at neutral pH. The amphiphilicity enabled the hydrogels to well retain and protect hydrophobic model drugs in the simulated gastric fluid, but efficiently release them in the simulated intestinal fluid. These results suggested that the pH-responsive amphiphilic hydrogels are promising candidates for oral delivery of hydrophobic drugs.

Journal article

Dong R, Liu R, Gaffney P, Schaepertoens M, Marchetti P, Williams C, Chen R, Livingston Aet al., 2018, 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

Wang S, Ha Y, Huang X, Chin B, Sim W, Chen Ret al., 2018, A new strategy for intestinal drug delivery via pH-responsive and membrane-active nanogels, ACS Applied Materials and Interfaces, Vol: 10, Pages: 36622-36627, ISSN: 1944-8244

Oral administration of hydrophobic and poorly intestinal epithelium-permeable drugs is a significant challenge. Herein, we report a new strategy to overcome this problem by using novel, pH-responsive, and membrane-active nanogels as drug carriers. Prepared by simple physical cross-linking of amphiphilic pseudopeptidic polymers with pH-controlled membrane-activity, the size and hydrophobicity–hydrophilicity balance of the nanogels could be well-tuned. Furthermore, the amphiphilic nanogels could release hydrophobic payloads and destabilize cell membranes at duodenum and jejunum pH 5.0–6.0, which suggests their great potential for intestinal drug delivery.

Journal article

Bachir ZA, Huang Y, He M, Huang L, Hou X, Chen R, Gao Fet al., 2018, Effects of PEG surface density and chain length on the pharmacokinetics and biodistribution of methotrexate-loaded chitosan nanoparticles, INTERNATIONAL JOURNAL OF NANOMEDICINE, Vol: 13, Pages: 5657-5671, ISSN: 1178-2013

Background: One of the most important aspects of drug delivery is extended nanoparticle (NP) residence time in vivo. Herein, we report a series of methotrexate (MTX)-loaded chitosan (CS) NPs coated with differently sized methoxy polyethylene glycol (mPEG) at different mPEG surface densities.Materials and methods: MTX was incorporated into NPs (112.8–171.2 nm in diameter) prepared from the resulting mPEG-g-CS. The NPs had a zeta potential of +7.4–35.0 mV and MTX loading efficiency of 17.1%–18.4%. MTX/mPEG-g-CS NPs showed an initial burst release of MTX followed by a sustained-release profile in PBS at pH 7.4.Results: The in vitro cellular uptake study showed that MTX accumulation in J774A.1 macrophage cells decreased with increasing the mPEG surface density or the mPEG molecular weight. The pharmacokinetic study on Sprague Dawley rats revealed an increase in AUC0–72 h (area under the plasma drug concentration–time curve over a period of 72 hours) with increasing the mPEG surface density or the mPEG molecular weight and a linear correlation between the mPEG surface density and AUC0–72 h.Conclusion: The biodistribution study on Institute of Cancer Research (ICR) mice revealed that MTX/mPEG-g-CS NPs significantly enhanced blood circulation time in the body and decreased accumulation in liver, spleen, and lung. These results suggest the potential of the mPEG-g-CS NPs as a promising candidate for drug delivery.

Journal article

Dong R, Chen R, Livingston A, 2018, Iterative synthesis of sequence-defined, multifunctional, biocompatible PEGs for biomedical applications, 256th National Meeting and Exposition of the American-Chemical-Society (ACS) - Nanoscience, Nanotechnology and Beyond, Publisher: AMER CHEMICAL SOC, ISSN: 0065-7727

Conference paper

Chen R, Chen S, Wu L, 2018, Poly(L-lysine isophthalamide) (PLP) Polymers with Hydrophobic Pendant Chains, WO 2018/011580

The present disclosure relates to the provision of novel biodegradable amphiphilic peptides and peptide analogues based on poly(L-lysine isophthalamide) (PLP) derivatives comprising hydrophobic chains and their use in the permeabilization of mammalian cells and delivery of agents, for example therapeutic agents, imaging agents and cell preservation agents.

Patent

Tascini AS, Noro MG, Chen R, Seddon JM, Bresme Fet al., 2018, Understanding the interactions between sebum triglycerides and water: a molecular dynamics simulation study., Physical Chemistry Chemical Physics, Vol: 20, Pages: 1848-1860, ISSN: 1463-9076

In recent years, sebum oil has been found to play a key role in the regulation of the hydration of the outermost layer of the skin, the stratum corneum. Understanding how a major component of the sebum oil, the triglyceride tri-cis-6-hexadecenoin (TG), interacts with water is an important step in gaining insight into the water regulation function of the sebum oil. Here we use molecular dynamics simulations to investigate the structural and interfacial properties of TG in bulk and at the air and water interface. Our model performs very well in reproducing experimental results, such as density, surface tensions and surface pressure area isotherms. We show that triglyceride molecules in the liquid phase assemble together, through the glycerol group, forming a single percolating network. TG-air interfaces orient the lipids with the interface enriched with the hydrophobic tails and the glycerol groups buried inside. When in contact with water, the TG molecules at the interface orient the glycerol group towards the water phase and adopt a characteristic trident conformation. Water is shown to penetrate the TG layer thanks to the interaction with the oxygen atoms of the TG molecules, which acts as a pathway for water diffusion. The activation energy for the passage of water is found to be ≈9.5kBT at 310 K, showing that the layer is permeable to water diffusion.

Journal article

Kluzek M, Tyler AII, Wang S, Chen R, Marques CM, Thalmann F, Seddon JM, Schmutz Met al., 2017, Influence of a pH-sensitive polymer on the structure of monoolein cubosomes., Soft Matter, Vol: 13, Pages: 7571-7577

Cubosomes consist in submicron size particles of lipid bicontinuous cubic phases stabilized by surfactant polymers. They provide an appealing road towards the practical use of lipid cubic phases for pharmaceutical and cosmetic applications, and efforts are currently being made to control the encapsulation and release properties of these colloidal objects. We overcome in this work the lack of sensitivity of monoolein cubosomes to pH conditions by using a pH sensitive polymer designed to strongly interact with the lipid structure at low pH. Our cryo-transmission electron microscope (cryo-TEM) and small-angle X-ray scattering (SAXS) results show that in the presence of the polymer the cubic phase structure is preserved at neutral pH, albeit with a larger cell size. At pH 5.5, in the presence of the polymer, the nanostructure of the cubosome particles is significantly altered, providing a pathway to design pH-responsive cubosomes for applications in drug delivery.

Journal article

Dong R, Chen R, Livingston A, 2017, Liquid-phase iterative synthesis with OSN: A flexible and scalable platform for precision synthetic macromolecules, 254th National Meeting and Exposition of the American-Chemical-Society (ACS) on Chemistry's Impact on the Global Economy, Publisher: AMER CHEMICAL SOC, ISSN: 0065-7727

Conference paper

Wang S, Chen R, 2017, pH-Responsive, Lysine-Based, Hyperbranched Polymers Mimicking Endosomolytic Cell-Penetrating Peptides for Efficient Intracellular Delivery, Chemistry of Materials, Vol: 29, Pages: 5806-5815, ISSN: 0897-4756

The insufficient delivery of biomacromolecular therapeutic agents into the cytoplasm of mammalian cells remains a major barrier to their pharmaceutical applications. Cell-penetrating peptides (CPPs) are considered as potential carriers for cytoplasmic delivery of macromolecular drugs. However, due to the positive charge of most CPPs, strong nonspecific cell membrane bindings may lead to relatively high toxicity. In this study, we report a series of anionic, CPP-mimicking, lysine-based hyperbranched polymers, which caused complete membrane disruption at late endosomal pH while remaining nonlytic at physiological pH. The pH-responsive conformational alterations and the multivalency effect of the hyperbranched structures were demonstrated to effectively facilitate their interaction with cell membranes, thus leading to significantly enhanced membrane-lytic activity compared with their linear counterpart. The unique structures and pH-responsive cell-penetrating abilities make the novel hyperbranched polymers promising candidates for cytoplasmic delivery of biomacromolecular payloads.

Journal article

Wang W, Guo Y, Tiede C, Chen S, Kopytynski M, Kong Y, Kulak A, Tomlinson D, Chen R, McPherson M, Zhou Det al., 2017, Ultraefficient Cap-Exchange Protocol To Compact Biofunctional Quantum Dots for Sensitive Ratiometric Biosensing and Cell Imaging., ACS Applied Materials & Interfaces, Vol: 9, Pages: 15232-15244, ISSN: 1944-8244

An ultraefficient cap-exchange protocol (UCEP) that can convert hydrophobic quantum dots (QDs) into stable, biocompatible, and aggregation-free water-dispersed ones at a ligand:QD molar ratio (LQMR) as low as 500, some 20-200-fold less than most literature methods, has been developed. The UCEP works conveniently with air-stable lipoic acid (LA)-based ligands by exploiting tris(2-carboxylethyl phosphine)-based rapid in situ reduction. The resulting QDs are compact (hydrodynamic radius, Rh, < 4.5 nm) and bright (retaining > 90% of original fluorescence), resist nonspecific adsorption of proteins, and display good stability in biological buffers even with high salt content (e.g., 2 M NaCl). These advantageous properties make them well suited for cellular imaging and ratiometric biosensing applications. The QDs prepared by UCEP using dihydrolipoic acid (DHLA)-zwitterion ligand can be readily conjugated with octa-histidine (His8)-tagged antibody mimetic proteins (known as Affimers). These QDs allow rapid, ratiometric detection of the Affimer target protein down to 10 pM via a QD-sensitized Förster resonance energy transfer (FRET) readout signal. Moreover, compact biotinylated QDs can be readily prepared by UCEP in a facile, one-step process. The resulting QDs have been further employed for ratiometric detection of protein, exemplified by neutravidin, down to 5 pM, as well as for fluorescence imaging of target cancer cells.

Journal article

Gaffney P, Livingston A, Chen R, Dong Ret al., 2017, Defined Monomer Sequence Polymers, WO/2017/042583

Processes of preparing defined monomer sequence polymers are disclosed, in which a backbone portion of the polymer is first prepared by performing one or more sequential monomeric coupling reactions with intervening membrane diafiltration purification/isolation steps, followed by a step of decorating the backbone portion with one or more side chains at predetermined positions along its length. The process represents an improvement on prior art techniques, which impose limitations on the size of the side chains that may be present. Defined monomer sequence polymers that are obtainable by the processes are also disclosed.

Patent

Chen S, Wang S, Kopytynski M, Bachelet M, Chen Ret al., 2017, Membrane-anchoring, comb-like pseudopeptides for efficient, pH-mediated membrane destabilization and intracellular delivery, ACS Applied Materials & Interfaces, Vol: 9, Pages: 8021-8029, ISSN: 1944-8244

Endosomal release has been identified as a rate-limiting step for intracellular delivery of therapeutic agents, in particular macromolecular drugs. Herein, we report a series of synthetic pH-responsive, membrane-anchoring polymers exhibiting dramatic endosomolytic activity for efficient intracellular delivery. The comb-like pseudopeptidic polymers were synthesized by grafting different amounts of decylamine (NDA), which act as hydrophobic membrane anchors, onto the pendant carboxylic acid groups of a pseudopeptide, poly(l-lysine iso-phthalamide). The effects of the hydrophobic relatively long alkyl side chains on aqueous solution properties, cell membrane destabilization activity, and in-vitro cytotoxicity were investigated. The optimal polymer containing 18 mol % NDA exhibited limited hemolysis at pH 7.4 but induced nearly complete membrane destabilization at endosomal pH within only 20 min. The mechanistic investigation of membrane destabilization suggests the polymer-mediated pore formation. It has been demonstrated that the polymer with hydrophobic side chains displayed a considerable endosomolytic ability to release endocytosed materials into the cytoplasm of various cell lines, which is of critical importance for intracellular drug delivery applications.

Journal article

Chen S, Chen R, 2016, A Virus-Mimicking, Endosomolytic Liposomal System for Efficient, pH-Triggered Intracellular Drug Delivery, ACS Applied Materials and Interfaces, Vol: 8, Pages: 22457-22467, ISSN: 1944-8244

A novel multifunctional liposomal delivery platform has been developed to resemble the structural and functional traits of an influenza virus. Novel pseudopeptides were prepared to mimic the pH-responsive endosomolytic behavior of influenza viral peptides through grafting a hydrophobic amino acid, l-phenylalanine, onto the backbone of a polyamide, poly(l-lysine isophthalamide), at various degrees of substitution. These pseudopeptidic polymers were employed to functionalize the surface of cholesterol-containing liposomes that mimic the viral envelope. By controlling the cholesterol proportion as well as the concentration and amphiphilicity of the pseudopeptides, the entire payload was rapidly released at endosomal pHs, while there was no release at pH 7.4. A pH-triggered, reversible change in liposomal size was observed, and the release mechanism was elucidated. In addition, the virus-mimicking nanostructures efficiently disrupted the erythrocyte membrane at pH 6.5 characteristic of early endosomes, while they showed negligible cytotoxic effects at physiological pH. The efficient intracellular delivery of the widely used anticancer drug doxorubicin (DOX) by the multifunctional liposomes was demonstrated, leading to significantly increased potency against HeLa cancer cells over the DOX-loaded bare liposomes. This novel virus-mimicking liposomal system, with the incorporated synergy of efficient liposomal drug release and efficient endosomal escape, is favorable for efficient intracellular drug delivery.

Journal article

Bachelet M, Chen R, 2016, Self-assembly of PEGylated gold nanoparticles with satellite structures as seeds, Chemical Communications, Vol: 52, Pages: 9542-9545, ISSN: 1364-548X

We report a very simple method for the self-assembly of spherical gold nanoparticles (AuNPs), coated with poly(ethylene glycol) (PEG), through a slow evaporation process at room temperature. Clusters of particles forming satellite structures may act as seeds for the self- assembly in a crystallization-like process. Based on the transmission electron microscopy (TEM) images obtained a mechanism for the self-assembly was suggested.

Journal article

Wang S, Liu X, Villar-Garcia IJ, Chen Ret al., 2016, Amino acid based hydrogels with dual responsiveness for oral drug delivery, Macromolecular Bioscience, Vol: 16, Pages: 1258-1264, ISSN: 1616-5195

This study reports a series of novel amino acid based dual-responsive hydrogels. Prepared by a facile one-pot 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) coupling reaction, the solid content, structure, and mechanical behavior of hydrogels could be easily adjusted by changing the concentrations of the polymers and the crosslinkers. With pH-responsive anionic pseudo-peptides as backbones and disulfide-containing l-cystine dimethyl ester as crosslinkers, these hydrogels are able to collapse and form relatively compact structure at an acidic pH, while swelled and partly dissociated at a neutral pH. Further addition of dithiothreitol (DTT) facilitated complete degradation of hydrogels. The high loading efficiency, rapid but complete triggered-release, and good biocompatibility make these hydrogels promising candidates for oral delivery.

Journal article

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