The Experts below are selected from a list of 233475 Experts worldwide ranked by ideXlab platform
Ruth Duncan - One of the best experts on this subject based on the ideXlab platform.
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dextrin phospholipase a2 synthesis and evaluation as a bioresponsive anticancer conjugate
Biomacromolecules, 2009Co-Authors: Elaine Lesley Ferguson, Ruth DuncanAbstract:There is still an urgent need for improved treatments for metastatic cancer. Although the phospholipase A2 (PLA2) crotoxin, an antitumor Protein that appears to act by interaction with epidermal growth factor receptors (EGFR), has recently shown activity in breast cancer in phase I clinical trials, it also displayed nonspecific neurotoxicity. Therefore, the aim of this study was to apply a novel concept called polymer-masked-unmasked-Protein Therapy (PUMPT) to give a bioresponsive dextrin−PLA2 conjugate that would reduce PLA2 systemic toxicity but retain antitumor activity following α-amylase triggered degradation of dextrin in the tumor interstitium. Dextrin (Mw ∼ 60000 g/mol; ∼22 mol % succinoylation) and PLA2 (from honey bee venom) were chosen as models for these initial studies, and the conjugates synthesized contained 6.1 wt % PLA2, with <1% free enzyme. The conjugate showed decreased (∼36%) enzyme activity compared to native PLA2, but activity was restored to ∼100% following incubation with α-amylas...
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dextrin phospholipase a2 synthesis and evaluation as a bioresponsive anticancer conjugate
Biomacromolecules, 2009Co-Authors: Elaine Lesley Ferguson, Ruth DuncanAbstract:There is still an urgent need for improved treatments for metastatic cancer. Although the phospholipase A2 (PLA2) crotoxin, an antitumor Protein that appears to act by interaction with epidermal growth factor receptors (EGFR), has recently shown activity in breast cancer in phase I clinical trials, it also displayed nonspecific neurotoxicity. Therefore, the aim of this study was to apply a novel concept called polymer-masked-unmasked- Protein Therapy (PUMPT) to give a bioresponsive dextrin-PLA2 conjugate that would reduce PLA2 systemic toxicity but retain antitumor activity following α-amylase triggered degradation of dextrin in the tumor interstitium. Dextrin (Mw ∼ 60000 g/mol; ∼22 mol % succinoylation) and PLA2 (from honey bee venom) were chosen as models for these initial studies, and the conjugates synthesized contained 6.1 wt % PLA2, with <1% free enzyme. The conjugate showed decreased (∼36%) enzyme activity compared to native PLA2, but activity was restored to ∼100% following ncubation with α-amylase. Whereas dextrin conjugation caused a marked reduction in PLA2's hemolytic activity, the conjugate was cytotoxic toward MCF-7, HT29, and B16F10 cells at a level that was comparable to, or greater than, that seen for free PLA2. In these cell lines, cytotoxicity showed partial correlation with the level of EGFR expression. The reduced toxicity and α-amylase triggered activity of the dextrin-PLA2 conjugate confirmed the potential of this approach for further development as a novel anticancer treatment. © 2009 American Chemical Society.
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dextrin rhegf conjugates as bioresponsive nanomedicines for wound repair
Journal of Controlled Release, 2008Co-Authors: Joseph Hardwicke, Elaine Lesley Ferguson, Ryan Moseley, Philip Stephens, D W P Thomas, Ruth DuncanAbstract:Growth factors are known to act in concert to promote wound repair, but their topical application rarely leads to a significant clinical improvement of chronic wounds due to premature inactivation in wound environment. The aim of this study was to synthesise a polymer-growth factor conjugate and investigate whether the novel concept called Polymer-masking-UnMasking-Protein Therapy (PUMPT) might be used to generate bioresponsive polymer therapeutics as nanomedicines able to promote tissue repair. Succinoylated dextrin (similar to 85,000 g/mol; similar to 19 mol% succinoylation), and rhEGF were chosen as a first model combination. The conjugate synthesised contained similar to 16%wt rhEGF and <1% free Protein. It exhibited increased stability towards proteolytic degradation by trypsin and the clinically relevant enzyme neutrophil elastase. The dextrin component was degraded on addition of alpha-amylase leading to sustained release of free rhEGF over time (52.7% release after 168 h). When biological activity was assessed ( +/-alpha-amylase) in proliferation assays using epidermoid carcinoma (HEp2) cells and HaCaT keratinocytes, as anticipated, polymer conjugation reduced rhEGF bioactivity (p=0.0035). However, exposure to physiological concentrations of alpha-amylase triggered dextrin degradation and this led to Protein unmasking with restoration of bioactivity to the level seen for unmodified rhEGE Indeed, prolongation of HEp2 proliferation was observed over 8 days. The inability of dextrin, succinoylated dextrin or alpha-amylase alone to induce proliferative effects, and the ability of alpha-amylase-exposed dextrin-rhEGF to induce phosphorylation of the epidermal growth factor receptor (EGFR) in HEp2 cells confirmed a mechanism of action by stimulation of classical signal transduction pathways. These observations suggest that this dextrin-rhEGF, and other dextrin-growth factor conjugates have potential for further development as bioresponsive nanomedicines for tissue repair.
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polymer masked unmasked Protein Therapy 1 bioresponsive dextrin trypsin and melanocyte stimulating hormone conjugates designed for α amylase activation
Biomacromolecules, 2008Co-Authors: Ruth Duncan, Helena R P Gilbert, Rodrigo J Carbajo, Maria J VicentAbstract:Polymer−Protein conjugation, particularly PEGylation, is well-established as a means of increasing circulation time, reducing antigenicity, and improving the stability of Protein therapeutics. However, PEG has limitations including lack of polymer biodegradability, and conjugation can diminish or modify Protein activity. The aim of this study was to explore a novel approach for polymer−Protein modification called polymer-masking-unmasking-Protein Therapy (PUMPT), the hypothesis being that conjugation of a biodegradable polymer to a Protein would protect it and mask activity in transit, while enabling controlled reinstatement of activity at the target site by triggered degradation of the polymeric component. To test this hypothesis, dextrin (α-1,4 polyglucose, a natural polymer degraded by α-amylase) was conjugated to trypsin as a model enzyme or to melanocyte stimulating hormone (MSH) as a model receptor−binding ligand. The effect of dextrin molecular weight (7700, and 47200 g/mol) and degree of succinoyl...
Zhiyuan Zhong - One of the best experts on this subject based on the ideXlab platform.
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small traceable endosome disrupting and bioresponsive click nanogels fabricated via microfluidics for cd44 targeted cytoplasmic delivery of therapeutic Proteins
ACS Applied Materials & Interfaces, 2019Co-Authors: Ke Huang, Chao Deng, Zhehong Zhu, Jiakun Guo, Guanglin Wang, Zhiyuan ZhongAbstract:Nanogels (NG) are among the most ideal cytoplasmic Protein delivery vehicles; however, their performance is suboptimal, partly owing to relatively big size, poor cell uptake, and endosomal entrapment. Here, we developed small, traceable, endosome-disrupting, and bioresponsive hyaluronic acid NG (HA-NG) for CD44-targeted intracellular delivery of therapeutic Proteins. With microfluidics and catalyst-free photo-click cross-linking, HA-NG with hydrodynamic diameters of ca. 80 and 150 nm, strong green fluorescence and efficient loading of various Proteins including saporin (Sap), cytochrome C, herceptin, immunoglobulin G (IgG), and bovine serum albumin could be fabricated. Interestingly, 80 nm-sized HA-NG revealed clearly better cellular uptake than its 150 nm counterparts in both CD44-negative U87 cancer cells and CD44-positive 4T1 and MDA-MB-231 cells. Moreover, small NG exhibited accelerated endosomal escape, which was further boosted by introducing GALA, a pH-sensitive fusogenic peptide. Accordingly, Sap-loaded small and GALA-functionalized HA-NG showed the highest cytotoxicity in CD44-positive MDA-MB-231, 4T1, A549, and SMMC-7721 cancer cells. The biodistribution studies demonstrated that 80 nm-sized HA-NG displayed significantly greater tumor uptake as well as penetration in MDA-MB-231 human breast tumor xenografts than its 150 nm counterparts, whereas the introduction of GALA had no detrimental effect on tumor accumulation. Small, endosome-disrupting, and bioresponsive HA-NG with easy and controlled fabrication hold a great potential for targeted Protein Therapy.
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saporin loaded cd44 and egfr dual targeted nanogels for potent inhibition of metastatic breast cancer in vivo
International Journal of Pharmaceutics, 2019Co-Authors: Jing Chen, Chao Deng, Lichen Yin, Zhiyuan ZhongAbstract:Abstract Metastasis poses a long-standing treatment challenge for many cancers including breast cancer. Once spreading out, cell-selective delivery of drug appears especially critical. Here, we report on epidermal growth factor receptor and CD44 dual-targeted hyaluronic acid nanogels (EGFR/CD44-NGs) that afford enhanced targetability and Protein Therapy for metastatic 4T1 breast cancer in vivo. Flow cytometry in CD44 and EGFR-positive 4T1 metastatic breast cancer cells showed over 6-fold higher cellular uptake of EGFR/CD44-NGs than mono-targeting CD44-NGs. MTT and scratch assays displayed that saporin-loaded EGFR/CD44-NGs (Sap-EGFR/CD44-NGs) was highly potent in inhibiting growth as well as migration of 4T1 cells in vitro, with an IC50 of 5.36 nM, which was 1.7-fold lower than that for Sap-CD44-NGs. In 4T1-luc metastatic breast cancer model in mice, Sap-EGFR/CD44-NGs exhibited significant inhibition of tumor metastasis to lung at a small dose of 3.33 nmol Sap equiv./kg. Increasing the dosage to 13.3 nmol Sap equiv./kg resulted in further reduced lung metastasis without causing notable adverse effects. These dual-targeted nanogels with improved cancer cell selectivity provide a novel platform for combating breast cancer metastasis.
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granzyme b loaded cell selective penetrating and reduction responsive polymersomes effectively inhibit progression of orthotopic human lung tumor in vivo
Journal of Controlled Release, 2018Co-Authors: Weijing Yang, Zhiyuan Zhong, Jian Zhang, Yaohua Wei, Liang Yang, Gert Storm, Fenghua MengAbstract:The clinical use of Protein therapeutics with intracellular targets is hampered by its in vivo fragility and low cell permeability. Here, we report that cell-selective penetrating and reduction-responsive polymersomes (CPRPs) mediate high-efficiency targeted delivery of granzyme B (GrB) to orthotopic human lung tumor in vivo. Model Protein studies using FITC-labeled cytochrome C (FITC-CC) revealed efficient and high Protein loading up to 17.2 wt% for CPRPs. FITC-CC-loaded CPRPs exhibited a small size of 82-90 nm, reduction-responsive Protein release, as well as greatly enhanced internalization and cytoplasmic Protein release in A549 lung cancer cells compared with the non-targeted FITC-CC-loaded RPs control. GrB-loaded CPRPs showed a high potency toward A549 lung cancer cells with a half maximal inhibitory concentration (IC50) of 20.7 nM. Under the same condition, free GrB was essentially non-toxic. Importantly, installing cell-selective penetrating peptide did not alter the circulation time but did enhance tumor accumulation of RPs. Orthotopic A549-Luc lung tumor-bearing nude mice administered with GrB-loaded CPRPs at a dosage of 2.88 nmol GrB equiv./kg showed complete tumor growth inhibition with little body weight loss throughout the treatment period, resulting in significantly improved survival rate over the non-targeted and non-treated controls. These cell-selective penetrating and reduction-responsive polymersomes provide a targeted Protein Therapy for cancers.
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Small-Sized and Robust Chimaeric Lipopepsomes: A Simple and Functional Platform with High Protein Loading for Targeted Intracellular Delivery of Protein Toxin in Vivo
2018Co-Authors: Min Qiu, Fenghua Meng, Chao Deng, Yaohua Wei, Zhenqi Zhang, Huanli Sun, Zhiyuan ZhongAbstract:How to chaperone Protein drugs into target tumor cells in vivo is a big challenge. Here, we report on small-sized and robust chimaeric vesicles (lipopepsomes) constructed with asymmetric poly(ethylene glycol)-b-poly(α-aminopalmitic acid)-b-poly(l-aspartic acid) triblock copolypeptide as a simple and functional platform for high loading and targeted intracellular delivery of saporin, a Protein toxin, in vivo. Cyclic RGD peptide-decorated chimaeric lipopepsomes (cRGD-CLP) following loading 2.0–9.4 wt % of model Protein FITC-labeled cytochrome C showed a small hydrodynamic size of 81–86 nm, enhanced internalization by αvβ3-overexpressing A549 lung tumor cells, as well as remarkable accumulation of 7.73% ID/g in the cancerous lung in mice. Saporin-loaded cRGD-CLP displayed a low half-maximal inhibitory concentration of 16.3 nM to A549 cancer cells. Intriguingly, saporin-loaded cRGD-CLP at 16.7 nmol saporin equiv/kg showed a high potency in treating orthotopically xenografted A549 lung tumors, suppressed tumor progression, and remarkably improved survival rate. These chimaeric lipopepsomes provide a versatile and potential means for targeted Protein Therapy of various malignancies
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ApolipoProtein E Peptide-Directed Chimeric Polymersomes Mediate an Ultrahigh-Efficiency Targeted Protein Therapy for Glioblastoma
2018Co-Authors: Yu Jiang, Jian Zhang, Fenghua Meng, Zhiyuan ZhongAbstract:The inability to cross the blood–brain barrier (BBB) prevents nearly all chemotherapeutics and biotherapeutics from the effective treatment of brain tumors, rendering few improvements in patient survival rates to date. Here, we report that apolipoProtein E peptide [ApoE, (LRKLRKRLL)2C] specifically binds to low-density lipoProtein receptor members (LDLRs) and mediates superb BBB crossing and highly efficient glioblastoma (GBM)-targeted Protein Therapy in vivo. The in vitro BBB model studies reveal that ApoE induces 2.2-fold better penetration of the immortalized mouse brain endothelial cell line (bEnd.3) monolayer for chimeric polymersomes (CP) compared to Angiopep-2, the best-known BBB-crossing peptide used in clinical trials for GBM Therapy. ApoE-installed CP (ApoE–CP) carrying saporin (SAP) displays a highly specific and potent antitumor effect toward U-87 MG cells with a low half-maximum inhibitory concentration of 14.2 nM SAP. Notably, ApoE–CP shows efficient BBB crossing as well as accumulation and penetration in orthotopic U-87 MG glioblastoma. The systemic administration of SAP-loaded ApoE–CP causes complete growth inhibition of orthotopic U-87 MG GBM without eliciting any observable adverse effects, affording markedly improved survival benefits. ApoE peptide provides an ultrahigh-efficiency targeting strategy for GBM Therapy
Elaine Lesley Ferguson - One of the best experts on this subject based on the ideXlab platform.
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dextrin phospholipase a2 synthesis and evaluation as a bioresponsive anticancer conjugate
Biomacromolecules, 2009Co-Authors: Elaine Lesley Ferguson, Ruth DuncanAbstract:There is still an urgent need for improved treatments for metastatic cancer. Although the phospholipase A2 (PLA2) crotoxin, an antitumor Protein that appears to act by interaction with epidermal growth factor receptors (EGFR), has recently shown activity in breast cancer in phase I clinical trials, it also displayed nonspecific neurotoxicity. Therefore, the aim of this study was to apply a novel concept called polymer-masked-unmasked- Protein Therapy (PUMPT) to give a bioresponsive dextrin-PLA2 conjugate that would reduce PLA2 systemic toxicity but retain antitumor activity following α-amylase triggered degradation of dextrin in the tumor interstitium. Dextrin (Mw ∼ 60000 g/mol; ∼22 mol % succinoylation) and PLA2 (from honey bee venom) were chosen as models for these initial studies, and the conjugates synthesized contained 6.1 wt % PLA2, with <1% free enzyme. The conjugate showed decreased (∼36%) enzyme activity compared to native PLA2, but activity was restored to ∼100% following ncubation with α-amylase. Whereas dextrin conjugation caused a marked reduction in PLA2's hemolytic activity, the conjugate was cytotoxic toward MCF-7, HT29, and B16F10 cells at a level that was comparable to, or greater than, that seen for free PLA2. In these cell lines, cytotoxicity showed partial correlation with the level of EGFR expression. The reduced toxicity and α-amylase triggered activity of the dextrin-PLA2 conjugate confirmed the potential of this approach for further development as a novel anticancer treatment. © 2009 American Chemical Society.
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dextrin phospholipase a2 synthesis and evaluation as a bioresponsive anticancer conjugate
Biomacromolecules, 2009Co-Authors: Elaine Lesley Ferguson, Ruth DuncanAbstract:There is still an urgent need for improved treatments for metastatic cancer. Although the phospholipase A2 (PLA2) crotoxin, an antitumor Protein that appears to act by interaction with epidermal growth factor receptors (EGFR), has recently shown activity in breast cancer in phase I clinical trials, it also displayed nonspecific neurotoxicity. Therefore, the aim of this study was to apply a novel concept called polymer-masked-unmasked-Protein Therapy (PUMPT) to give a bioresponsive dextrin−PLA2 conjugate that would reduce PLA2 systemic toxicity but retain antitumor activity following α-amylase triggered degradation of dextrin in the tumor interstitium. Dextrin (Mw ∼ 60000 g/mol; ∼22 mol % succinoylation) and PLA2 (from honey bee venom) were chosen as models for these initial studies, and the conjugates synthesized contained 6.1 wt % PLA2, with <1% free enzyme. The conjugate showed decreased (∼36%) enzyme activity compared to native PLA2, but activity was restored to ∼100% following incubation with α-amylas...
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dextrin rhegf conjugates as bioresponsive nanomedicines for wound repair
Journal of Controlled Release, 2008Co-Authors: Joseph Hardwicke, Elaine Lesley Ferguson, Ryan Moseley, Philip Stephens, D W P Thomas, Ruth DuncanAbstract:Growth factors are known to act in concert to promote wound repair, but their topical application rarely leads to a significant clinical improvement of chronic wounds due to premature inactivation in wound environment. The aim of this study was to synthesise a polymer-growth factor conjugate and investigate whether the novel concept called Polymer-masking-UnMasking-Protein Therapy (PUMPT) might be used to generate bioresponsive polymer therapeutics as nanomedicines able to promote tissue repair. Succinoylated dextrin (similar to 85,000 g/mol; similar to 19 mol% succinoylation), and rhEGF were chosen as a first model combination. The conjugate synthesised contained similar to 16%wt rhEGF and <1% free Protein. It exhibited increased stability towards proteolytic degradation by trypsin and the clinically relevant enzyme neutrophil elastase. The dextrin component was degraded on addition of alpha-amylase leading to sustained release of free rhEGF over time (52.7% release after 168 h). When biological activity was assessed ( +/-alpha-amylase) in proliferation assays using epidermoid carcinoma (HEp2) cells and HaCaT keratinocytes, as anticipated, polymer conjugation reduced rhEGF bioactivity (p=0.0035). However, exposure to physiological concentrations of alpha-amylase triggered dextrin degradation and this led to Protein unmasking with restoration of bioactivity to the level seen for unmodified rhEGE Indeed, prolongation of HEp2 proliferation was observed over 8 days. The inability of dextrin, succinoylated dextrin or alpha-amylase alone to induce proliferative effects, and the ability of alpha-amylase-exposed dextrin-rhEGF to induce phosphorylation of the epidermal growth factor receptor (EGFR) in HEp2 cells confirmed a mechanism of action by stimulation of classical signal transduction pathways. These observations suggest that this dextrin-rhEGF, and other dextrin-growth factor conjugates have potential for further development as bioresponsive nanomedicines for tissue repair.
Fenghua Meng - One of the best experts on this subject based on the ideXlab platform.
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granzyme b loaded cell selective penetrating and reduction responsive polymersomes effectively inhibit progression of orthotopic human lung tumor in vivo
Journal of Controlled Release, 2018Co-Authors: Weijing Yang, Zhiyuan Zhong, Jian Zhang, Yaohua Wei, Liang Yang, Gert Storm, Fenghua MengAbstract:The clinical use of Protein therapeutics with intracellular targets is hampered by its in vivo fragility and low cell permeability. Here, we report that cell-selective penetrating and reduction-responsive polymersomes (CPRPs) mediate high-efficiency targeted delivery of granzyme B (GrB) to orthotopic human lung tumor in vivo. Model Protein studies using FITC-labeled cytochrome C (FITC-CC) revealed efficient and high Protein loading up to 17.2 wt% for CPRPs. FITC-CC-loaded CPRPs exhibited a small size of 82-90 nm, reduction-responsive Protein release, as well as greatly enhanced internalization and cytoplasmic Protein release in A549 lung cancer cells compared with the non-targeted FITC-CC-loaded RPs control. GrB-loaded CPRPs showed a high potency toward A549 lung cancer cells with a half maximal inhibitory concentration (IC50) of 20.7 nM. Under the same condition, free GrB was essentially non-toxic. Importantly, installing cell-selective penetrating peptide did not alter the circulation time but did enhance tumor accumulation of RPs. Orthotopic A549-Luc lung tumor-bearing nude mice administered with GrB-loaded CPRPs at a dosage of 2.88 nmol GrB equiv./kg showed complete tumor growth inhibition with little body weight loss throughout the treatment period, resulting in significantly improved survival rate over the non-targeted and non-treated controls. These cell-selective penetrating and reduction-responsive polymersomes provide a targeted Protein Therapy for cancers.
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Small-Sized and Robust Chimaeric Lipopepsomes: A Simple and Functional Platform with High Protein Loading for Targeted Intracellular Delivery of Protein Toxin in Vivo
2018Co-Authors: Min Qiu, Fenghua Meng, Chao Deng, Yaohua Wei, Zhenqi Zhang, Huanli Sun, Zhiyuan ZhongAbstract:How to chaperone Protein drugs into target tumor cells in vivo is a big challenge. Here, we report on small-sized and robust chimaeric vesicles (lipopepsomes) constructed with asymmetric poly(ethylene glycol)-b-poly(α-aminopalmitic acid)-b-poly(l-aspartic acid) triblock copolypeptide as a simple and functional platform for high loading and targeted intracellular delivery of saporin, a Protein toxin, in vivo. Cyclic RGD peptide-decorated chimaeric lipopepsomes (cRGD-CLP) following loading 2.0–9.4 wt % of model Protein FITC-labeled cytochrome C showed a small hydrodynamic size of 81–86 nm, enhanced internalization by αvβ3-overexpressing A549 lung tumor cells, as well as remarkable accumulation of 7.73% ID/g in the cancerous lung in mice. Saporin-loaded cRGD-CLP displayed a low half-maximal inhibitory concentration of 16.3 nM to A549 cancer cells. Intriguingly, saporin-loaded cRGD-CLP at 16.7 nmol saporin equiv/kg showed a high potency in treating orthotopically xenografted A549 lung tumors, suppressed tumor progression, and remarkably improved survival rate. These chimaeric lipopepsomes provide a versatile and potential means for targeted Protein Therapy of various malignancies
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ApolipoProtein E Peptide-Directed Chimeric Polymersomes Mediate an Ultrahigh-Efficiency Targeted Protein Therapy for Glioblastoma
2018Co-Authors: Yu Jiang, Jian Zhang, Fenghua Meng, Zhiyuan ZhongAbstract:The inability to cross the blood–brain barrier (BBB) prevents nearly all chemotherapeutics and biotherapeutics from the effective treatment of brain tumors, rendering few improvements in patient survival rates to date. Here, we report that apolipoProtein E peptide [ApoE, (LRKLRKRLL)2C] specifically binds to low-density lipoProtein receptor members (LDLRs) and mediates superb BBB crossing and highly efficient glioblastoma (GBM)-targeted Protein Therapy in vivo. The in vitro BBB model studies reveal that ApoE induces 2.2-fold better penetration of the immortalized mouse brain endothelial cell line (bEnd.3) monolayer for chimeric polymersomes (CP) compared to Angiopep-2, the best-known BBB-crossing peptide used in clinical trials for GBM Therapy. ApoE-installed CP (ApoE–CP) carrying saporin (SAP) displays a highly specific and potent antitumor effect toward U-87 MG cells with a low half-maximum inhibitory concentration of 14.2 nM SAP. Notably, ApoE–CP shows efficient BBB crossing as well as accumulation and penetration in orthotopic U-87 MG glioblastoma. The systemic administration of SAP-loaded ApoE–CP causes complete growth inhibition of orthotopic U-87 MG GBM without eliciting any observable adverse effects, affording markedly improved survival benefits. ApoE peptide provides an ultrahigh-efficiency targeting strategy for GBM Therapy
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bioresponsive chimaeric nanopolymersomes enable targeted and efficacious Protein Therapy for human lung cancers in vivo
Chemistry of Materials, 2017Co-Authors: Weijing Yang, Fenghua Meng, Yifeng Xia, Yan Zou, Jian Zhang, Zhiyuan ZhongAbstract:Rapidly evolving Protein technology has generated hundreds of therapeutic Proteins that are promising for treating various human diseases. The clinical use of Protein drugs remains, however, limited due to the absence of viable vehicles. Here, we report that anisamide-functionalized bioresponsive chimaeric nanopolymersomes (Anis-BCPs) can efficiently load granzyme B (GrB), a potent apoptotic Protein, and enable targeted and efficacious Protein Therapy for H460 human lung cancer in vivo. Anis-BCPs are readily obtained from poly(ethylene glycol)-b-poly(N-2-hydroxypropyl methacrylamide-g-lipoic acid)-b-poly(acrylic acid) triblock copolymer. Notably, GrB-loaded Anis-BCPs a display superior antitumor effect toward sigma receptor-overexpressing H460 lung cancer cells (IC50 = 7.8 nM). The in vivo studies reveal that Anis-BCPs have a long circulation time and remarkable tumor accumulation. Interestingly, GrB-loaded Anis-BCPs at 6.24 nmol GrB equiv/kg dose, given either in four injections or one single injection, ...
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Bioresponsive Chimaeric Nanopolymersomes Enable Targeted and Efficacious Protein Therapy for Human Lung Cancers in Vivo
2017Co-Authors: Weijing Yang, Fenghua Meng, Yifeng Xia, Yan Zou, Jian Zhang, Zhiyuan ZhongAbstract:Rapidly evolving Protein technology has generated hundreds of therapeutic Proteins that are promising for treating various human diseases. The clinical use of Protein drugs remains, however, limited due to the absence of viable vehicles. Here, we report that anisamide-functionalized bioresponsive chimaeric nanopolymersomes (Anis-BCPs) can efficiently load granzyme B (GrB), a potent apoptotic Protein, and enable targeted and efficacious Protein Therapy for H460 human lung cancer in vivo. Anis-BCPs are readily obtained from poly(ethylene glycol)-b-poly(N-2-hydroxypropyl methacrylamide-g-lipoic acid)-b-poly(acrylic acid) triblock copolymer. Notably, GrB-loaded Anis-BCPs a display superior antitumor effect toward sigma receptor-overexpressing H460 lung cancer cells (IC50 = 7.8 nM). The in vivo studies reveal that Anis-BCPs have a long circulation time and remarkable tumor accumulation. Interestingly, GrB-loaded Anis-BCPs at 6.24 nmol GrB equiv/kg dose, given either in four injections or one single injection, effectively inhibit H460 tumor growth and significantly improve the survival rate for mice. These robust, bioresponsive, and nontoxic chimaeric nanopolymersomes provide a potential platform for cancer Protein Therapy as well as basic research on intracellular functional Proteins
Dean J. Burkin - One of the best experts on this subject based on the ideXlab platform.
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Laminin-111 Protein Therapy Reduces Muscle Pathology and Improves Viability of a Mouse Model of Merosin-Deficient Congenital Muscular Dystrophy
The American journal of pathology, 2012Co-Authors: Jachinta E. Rooney, Bradley L. Hodges, Jolie R. Knapp, Ryan D. Wuebbles, Dean J. BurkinAbstract:Merosin-deficient congenital muscular dystrophy type 1A (MDC1A) is a lethal muscle-wasting disease that is caused by mutations in the LAMA2 gene, resulting in the loss of laminin-α2 Protein. MDC1A patients exhibit severe muscle weakness from birth, are confined to a wheelchair, require ventilator assistance, and have reduced life expectancy. There are currently no effective treatments or cures for MDC1A. Laminin-α2 is required for the formation of heterotrimeric laminin-211 (ie, α2, β1, and γ1) and laminin-221 (ie, α2, β2, and γ1), which are major constituents of skeletal muscle basal lamina. Laminin-111 (ie, α1, β1, and γ1) is the predominant laminin isoform in embryonic skeletal muscle and supports normal skeletal muscle development in laminin-α2–deficient muscle but is absent from adult skeletal muscle. In this study, we determined whether treatment with Engelbreth-Holm-Swarm–derived mouse laminin-111 Protein could rescue MDC1A in the dyW−/− mouse model. We demonstrate that laminin-111 Protein systemically delivered to the muscles of laminin-α2–deficient mice prevents muscle pathology, improves muscle strength, and dramatically increases life expectancy. Laminin-111 also prevented apoptosis in laminin-α2–deficient mouse muscle and primary human MDC1A myogenic cells, which indicates a conserved mechanism of action and cross-reactivity between species. Our results demonstrate that laminin-111 can serve as an effective Protein substitution Therapy for the treatment of muscular dystrophy in the dyW−/− mouse model and establish the potential for its use in the treatment of MDC1A.
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laminin 111 Protein Therapy prevents muscle disease in the mdx mouse model for duchenne muscular dystrophy
Proceedings of the National Academy of Sciences of the United States of America, 2009Co-Authors: Jachinta E. Rooney, Praveen B. Gurpur, Dean J. BurkinAbstract:Duchenne muscular dystrophy (DMD) is a devastating neuromuscular disease caused by mutations in the gene encoding dystrophin. Loss of dystrophin results in reduced sarcolemmal integrity and increased susceptibility to muscle damage. The α7β1-integrin is a laminin-binding Protein up-regulated in the skeletal muscle of DMD patients and in the mdx mouse model. Transgenic overexpression of the α7-integrin alleviates muscle disease in dystrophic mice, making this gene a target for pharmacological intervention. Studies suggest laminin may regulate α7-integrin expression. To test this hypothesis, mouse and human myoblasts were treated with laminin and assayed for α7-integrin expression. We show that laminin-111 (α1, β1, γ1), which is expressed during embryonic development but absent in normal or dystrophic skeletal muscle, increased α7-integrin expression in mouse and DMD patient myoblasts. Injection of laminin-111 Protein into the mdx mouse model of DMD increased expression of α7-integrin, stabilized the sarcolemma, restored serum creatine kinase to wild-type levels, and protected muscle from exercised-induced damage. These findings demonstrate that laminin-111 is a highly potent therapeutic agent for the mdx mouse model of DMD and represents a paradigm for the systemic delivery of extracellular matrix Proteins as therapies for genetic diseases.
