90 results found
Xiang Y, Wang B, Yang W, et al., 2024, Mitocytosis Mediated by an Enzyme-Activable Mitochondrion-Disturbing Polymer-Drug Conjugate Enhances Active Penetration in Glioblastoma Therapy., Adv Mater
The application of nanomedicines for glioblastoma (GBM) therapy is hampered by the blood-brain barrier (BBB) and the dense glioblastoma tissue. To achieve efficient BBB crossing and deep GBM penetration, this work demonstrates a strategy of active transcellular transport of a mitochondrion-disturbing nanomedicine, pGBEMA22 -b-pSSPPT9 (GBEPPT), in the GBM tissue through mitocytosis. GBEPPT is computer-aided designed and prepared by self-assembling a conjugate of an amphiphilic block polymer and a drug podophyllotoxin (PPT). When GBEPPT is delivered to the tumor site, overexpressed γ-glutamyl transpeptidase (GGT) on the brain-blood endothelial cell, or the GBM cell triggered enzymatic hydrolysis of γ-glutamylamide on GBEPPT to reverse its negative charge to positive. Positively charged GBEPPT rapidly enter into the cell and target the mitochondria. These GBEPPT disturb the homeostasis of mitochondria, inducing mitocytosis-mediated extracellular transport of GBEPPT to the neighboring cells via mitosomes. This intracellular-to-intercellular delivery cycle allows GBEPPT to penetrate deeply into the GBM parenchyma, and exert sustainable action of PPT released from GBEPPT on the tumor cells along its penetration path at the tumor site, thus improving the anti-GBM effect. The process of mitocytosis mediated by the mitochondrion-disturbing nanomedicine may offer great potential in enhancing drug penetration through malignant tissues, especially poorly permeable solid tumors.
Liu X, Liu Y, Yang X, et al., 2023, Potentiating the Immune Responses of HBsAg-VLP Vaccine Using a Polyphosphoester-Based Cationic Polymer Adjuvant, ACS APPLIED MATERIALS & INTERFACES, Vol: 15, Pages: 48871-48881, ISSN: 1944-8244
Kaur A, Darvill D, Xiang S, et al., 2023, Development of nanopackaging for storage and transport of loaded lipid nanoparticles, Nano Letters, Vol: 23, Pages: 6760-6767, ISSN: 1530-6984
Easily deploying new vaccines globally to combat disease outbreaks has been highlighted as a major necessity by the World Health Organization. RNA-based vaccines using lipid nanoparticles (LNPs) as a drug delivery system were employed to great effect during the recent COVID-19 pandemic. However, LNPs are still unstable at room temperature and agglomerate over time during storage, rendering them ineffective for intracellular delivery. We demonstrate the suitability of nanohole arrays (nanopackaging) as patterned surfaces to separate and store functionalized LNPs (fLNPs) in individual recesses, which can be expanded to other therapeutics. Encapsulating calcein as a model drug, we show through confocal microscopy the effective loading of fLNPs into our nanopackaging for both wet and dry systems. We prove quantifiably pH-mediated capture and subsequent unloading of over 30% of the fLNPs using QCM-D on alumina surfaces altering the pH from 5.5 to 7, displaying controllable storage at the nanoscale.
Li X, Duan Z, Chen X, et al., 2023, Impairing Tumor Metabolic Plasticity via a Stable Metal‐Phenolic‐Based Polymeric Nanomedicine to Suppress Colorectal Cancer, Advanced Materials, Vol: 35, ISSN: 0935-9648
<jats:title>Abstract</jats:title><jats:p>Targeting metabolic vulnerability of tumor cells is a promising anticancer strategy. However, the therapeutic efficacy of existing metabolism‐regulating agents is often compromised due to tolerance resulting from tumor metabolic plasticity, as well as their poor bioavailability and tumor‐targetability. Inspired by the inhibitive effect of <jats:italic>N</jats:italic>‐ethylmaleimide on the mitochondrial function, a dendronized‐polymer‐functionalized metal‐phenolic nanomedicine (pOEG‐<jats:italic>b</jats:italic>‐D‐SH@NP) encapsulating maleimide‐modified doxorubicin (Mal‐DOX) is developed to enable improvement in the overall delivery efficiency and inhibition of the tumor metabolism via multiple pathways. It is observed that Mal‐DOX and its derived nanomedicine induces energy depletion of CT26 colorectal cancer cells more efficiently than doxorubicin, and shifts the balance of programmed cell death from apoptosis toward necroptosis. Notably, pOEG‐<jats:italic>b</jats:italic>‐D‐SH@NP simultaneously inhibits cellular oxidative phosphorylation and glycolysis, thus potently suppressing cancer growth and peritoneal intestinal metastasis in mouse models. Overall, the study provides a promising dendronized‐polymer‐derived nanoplatform for the treatment of cancers through impairing metabolic plasticity.</jats:p>
Zhu GH, Azharuddin M, Pramanik B, et al., 2023, Feasibility of coacervate-like nanostructure for instant drug nanoformulation, ACS Applied Materials & Interfaces, Vol: 15, Pages: 17485-17494, ISSN: 1944-8244
Despite the enormous advancements in nanomedicine research, a limited number of nano formulations are available on the market and translated to clinics. Easily scalable, sustainable, cost-effective manufacturing strategy and long-term stability for storage are crucial for successful translation. Here, we report a system and method to instantly formulate NF achieved with a nanoscale polyelectrolyte coacervate-like system, consisting of anionic pseudo-peptide poly (L-lysine iso-phthalamide) derivatives, polyethylenimine, and doxorubicin (Dox) via simple ‘mix-and-go’ addition of precursor solutions in seconds. The coacervate-like nanosystem shows enhanced intracellular delivery of Dox to patient-derived multidrug-resistant (MDR) cells in 3D tumor spheroids. The results demonstrate the feasibility of an instant drug formulation using a coacervate-like nanosystem. We envisage that this technique can be widely utilised in the nanomedicine field to bypass the special requirement of large-scale production and elongated shelf-life of nanomaterials.
Zhang Y, Zhou J, Chen X, et al., 2023, Modulating tumor-stromal crosstalk via a redox-responsive nanomedicine for combination tumor therapy, Journal of Controlled Release, Vol: 356, Pages: 525-541, ISSN: 0168-3659
Yan D, Lu H, Kaur A, et al., 2023, Development and optimisation of cationic lipid nanoparticles for mRNA delivery
Messenger RNA (mRNA) has been proposed as a therapeutic agent for various diseases, including cancer. To ensure effective transfection of cancer cells, mRNA needs to be transported with a delivery system that protects its integrity and functionality. In this regard, cationic lipid nanoparticles composed of dioleoylphosphatidylethanolamine (DOPE) and 3β-[N-(N’,N’-dimethylaminoethane)-carbamoyl] cholesterol (DC-Chol) have emerged as common vectors to deliver mRNA. In this project, we aim to use luciferase mRNA as a reporter to synthesise mRNA-loaded cationic lipid nanoparticles, and optimise their mRNA encapsulation and transfection efficiency in ovarian cancer cells. The optimisation process included: 1) adjusting the lipid formulation; 2) adjusting the input mRNA concentration before lipid nanoparticle extrusion; and 3) adjusting the extrusion methods. After optimisation, the encapsulation efficiency was optimised to 62%, thus achieving a relatively high transfection luminescence signal (9.4 times compared to baseline). The lipid nanoparticles also demonstrated stable physical characteristics and high biocompatibility (above 75% cell viability after treatment) within 24 hours. Overall, this project evaluated the synthesis of DOPE/DC-Chol cationic lipid nanoparticles, and optimised their mRNA encapsulation and transfection efficiency in ovarian cancer cell lines. The optimised lipid nanoparticles can be utilised as an ideal system for mRNA delivery, which could be further developed as a potential platform for the immunotherapy in ovarian cancer.
Chen S, Morrison G, Liu W, et al., 2022, A pH-responsive, endosomolytic liposome functionalized with membrane-anchoring, comb-like pseudopeptides for enhanced intracellular delivery and cancer treatment, Biomaterials Science, Vol: 10, Pages: 6718-6730, 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.
Huang Y, Jiang J, Ren J, et 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.
Zheng X, Pan D, Zhu G, et al., 2022, A Dendritic Polymer‐Based Nanosystem Mediates Drug Penetration and Irreversible Endoplasmic Reticulum Stresses in Tumor via Neighboring Effect, Advanced Materials, Vol: 34, ISSN: 0935-9648
<jats:title>Abstract</jats:title><jats:p>Nanoparticles (NPs)‐based cancer therapeutics are generally impeded by poor drug penetration into solid tumors due to their dense tumor extracellular matrix (ECM). Herein, pH/redox‐responsive dendritic polymer‐based NPs are developed to amplify the neighboring effect for improving drug penetration and driving cell apoptosis via combination therapy. Pyropheophorbide a (Ppa) is conjugated with PEGylated dendritic peptides via disulfide bonds and doxorubicin (DOX) encapsulated in the conjugate to construct dual‐responsive NPs, PDPP@D. Delayed released DOX and Ppa from PDPP@D exert their combination therapeutic effect to induce cell apoptosis, and then they are liberated out of dying cells to amplify the neighboring effect, resulting in their diffusion through the dense ECM and penetration into solid tumors. Transcriptome studies reveal that PDPP@D leads to irreversible stress on the endoplasmic reticulum and inhibits cell protection through blocking the IRE1‐dependent survival pathway and unleashing the DR5‐mediated caspase activity to promote cell death. The strategy of amplifying the neighboring effect of NPs through combination therapy may offer great potential in enhancing drug penetration and eradicating solid tumors.</jats:p>
Gu L, Duan Z, Chen X, et 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.
Luo Q, Duan Z, Li X, et 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.
Li Y, Duan Z, Pan D, et al., 2022, Attenuating metabolic competition of tumor cells for favoring the nutritional demand of immune cells by a branched polymeric drug delivery system, Advanced Materials, Vol: 35, Pages: 1-14, ISSN: 0935-9648
Tumor cells are dominant in the nutritional competition in the tumor microenvironment (TME), and their metabolic abnormalities often lead to microenvironmental acidosis and nutrient deprivation, thereby impairing the function of immune cells and diminishing the anti-tumor therapeutic effect. Herein, we report a branched polymeric conjugate and its efficacy in attenuating the metabolic competition of tumor cells. Compared with the control nanoparticles prepared from its linear counterpart, the branched conjugate-based nanoparticles (branched NPs) could more efficiently accumulate in the tumor tissue and interfere with the metabolic processes of tumor cells to increase the concentration of essential nutrients and reduce the level of immunosuppressive metabolites in the TME, thus creating a favorable environment for infiltrated immune cells. Its combined treatment with an immune checkpoint inhibitor (ICI) achieved an enhanced anti-tumor effect. Our work presents a promising approach for targeting the metabolic competition in the TME to enhance the chemo-immunotherapeutic effect against cancers.
Pan D, Zheng X, Zhang L, et 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.
Cai H, Tan P, Chen X, et 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.
Gu B, Huang Y, Manchester E, et 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.
Chen R, Liu X, Shattock R, et al., 2021, Sub-micron particle
Chen R, Bhamra A, Shattock R, et al., 2021, Payload delivery system
Shmool T, Bhamra A, Chen R, et al., 2021, Stable composition
Tan P, Cai H, Wei Q, et 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.
Huang Y, Gu B, Salles II, et 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.
Huang Y, Wang Z, Zhang G, et 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.
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.
Chen R, Yu L, Tang Y, 2020, Polymer
Chen R, Huang Y, Xu XY, et al., 2020, Red Blood Cell-Derived Vesicle
Chen S, Wu L, Ren J, et 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.
Tascini AS, Wang S, Seddon JM, et 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.
Huang Y, Qiu F, Chen R, et 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.
Li L, Xiao B, Mu J, et 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.
Kopytynski M, Chen S, Legg S, et 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.
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