European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V, 2016
Asiaticoside is a natural compound possessing diverse pharmacological effects with great potentia... more Asiaticoside is a natural compound possessing diverse pharmacological effects with great potential for clinical use. However, the low solubility and oil-water partition coefficient of asiaticoside lead to reduced effect and limited application. This study aims to construct a porous microsphere for the sustained release of asiaticoside to improve its absorption and enhance the therapeutic effects. Parameters of the formulations, including the drug to polymer ratio, solvent amounts of the inner and external phases, the stirring speed for preparation, and the drug entrapment efficiency were investigated and optimized. Particle size, morphology, pores structure, and Fourier transform infrared spectrum of the microsphere were characterized. The release kinetics and cellular uptake profiles of the asiaticoside-microspheres were examined. The therapeutic effects of asiaticoside-microspheres on wound healing and skin appendages regeneration were investigated in vitro & in vivo. Results show...
Melanin is the one of most important pigments for skin color in mammals. Excessive biosynthesis o... more Melanin is the one of most important pigments for skin color in mammals. Excessive biosynthesis of melanin induces various pigment disorders. Much effort has been made to develop regulators to minimize skin pigmentation abnormalities. However, only a few of them are used, primarily because of safety concerns and low efficiency. In this study, we aimed to construct a novel nanosphere-gel for sequential delivery of salidroside and paeonol, to investigate the synergistic effects of these drugs in anti-melanogenesis, and to decrease their potential for toxicity in high dosage. Nanospheres were prepared and characterized for their particle size, polydispersity index, zeta potential, and morphological properties. The optimized nanospheres were incorporated in carbomer hydrogel with both paeonol and salidroside entrapped to form a dual drug-releasing nanosphere-gel. With this nanosphere-gel, rapid release of salidroside from the hydrogel followed by sustained release of paeonol from the na...
Most nonviral gene delivery systems are not efficient enough to manipulate the difficult-to-trans... more Most nonviral gene delivery systems are not efficient enough to manipulate the difficult-to-transfect cell types, including non-dividing, primary, neuronal or stem cells, due to a lack of an intrinsic capacity to enter the membrane and nucleus, release its DNA payload, and activate transcription. Noble metal nanoclusters have emerged as a fascinating area of widespread interest in nanomaterials. Herein, we report the synthesis of the TAT peptide conjugated cationic noble metal nanoparticles (metal NPs@PEI-TAT) as highly efficient carriers for gene delivery to stem cells. The metal NPs@PEI-TAT integrate the advantages of metal NPs and peptides: the presence of metal NPs can effectively decrease the cytotoxicity of cationic molecules, making it possible to apply them in biological systems, while the cell penetrating peptides are essential for enhanced cellular and nucleus entry to achieve high transfection efficiency. Our studies provide strong evidence that the metal NPs@PEI-TAT can be engineered as gene delivery agents for stem cells and subsequently enhance their directed differentiation for biomedical application.
Gold nanoparticles (AuNPs) have emerged as attractive non-viral gene vectors. However their appli... more Gold nanoparticles (AuNPs) have emerged as attractive non-viral gene vectors. However their application in regenerative medicine is still limited partially due to a lack of an intrinsic capacity to transfect difficult-to-transfect cells such as primary cells or stem cells. In current study, we report the synthesis of antimicrobial peptide conjugated cationic AuNPs (AuNPs@PEP) as highly efficient carriers for gene delivery to stem cells with antibacterial ability. The AuNPs@PEP integrate the advantages of cationic AuNPs and antibacterial peptides: the presence of cationic AuNPs can effectively condense DNA and the antimicrobial peptides are essential for the cellular & nucleus entry enhancement to achieve high transfection efficiency and antibacterial ability. As a result, antimicrobial peptides conjugated AuNPs significantly promoted the gene transfection efficiency in rat mesenchymal stem cells than pristine AuNPs, with a similar extent to those expressed by TAT (a well-known cell-...
Systemic administration of chemotherapeutic agents can cause indiscriminate drug distribution and... more Systemic administration of chemotherapeutic agents can cause indiscriminate drug distribution and severe toxicity. Until now, encapsulation and targeting of drugs have typically relied on synthetic vehicles, which cannot minimize the clearance by the renal system and may also increase the risk of chemical side effects. Cell membrane capsules (CMCs) provide a generic and far more natural approach to the challenges of drug encapsulation and delivery in vivo. Here aptamer AS1411, which can recognize and bind overexpressed nucleolin on a cancer cell membrane, was chemically conjugated onto CMCs. As a result, AS1411 modified CMCs showed enhanced ingestion in certain cancer cells in vitro and accumulation in mouse cancer xenografts in vivo. Chemotherapeutics and contrast agents with therapeutically significant concentrations can be packaged into CMCs by reversible permeating their plasma membranes. The systematic administration of cancer targeting CMCs loaded with doxorubicin hydrochlorid...
Repair of deep wounds by cell transplantation strongly depends on angiogenesis and on the regener... more Repair of deep wounds by cell transplantation strongly depends on angiogenesis and on the regeneration of skin and appendages. In this study, plasmid DNA encoding vascular endothelial growth factor-165 (VEGF-165) was transduced into bone-marrow mesenchymal stem cells (MSCs) using a nonviral vector, β-cyclodextrin-linked polyethylenimine, to enhance angiogenic capacity. The effects of MSCs administered by intradermal injection or transplantation on wound closure were compared in a full-thickness excision wound model. The results showed that the MSC-seeded sponge had significantly stronger acceleration in wound closure than the MSC injection. The effects on wound repair and regeneration of transplanted MSCs and pDNA-VEGF1 65-transfected MSCs (TMSCs) with gelatin/β-tricalcium phosphate scaffold were also investigated. Compared with MSC transplantation, TMSC transplantation showed higher efficacy in stimulating wound closure, promoting dermal collagen synthesis and regulating the deposition of newly formed collagen. In addition, the angiogenic capacity of the TMSCs was higher than that of the MSCs. The results indicate that the nonviral genetic engineering of the MSCs is a promising strategy to enhance the angiogenic capacity of MSCs for wound repair and angiogenesis. Functional gene-activated MSCs may be used as cost-effective and accessible seed cells for skin tissue engineering and as novel carriers for wound gene therapy.
Drug delivery to avascular, negatively charged tissues like cartilage remains a challenge. The co... more Drug delivery to avascular, negatively charged tissues like cartilage remains a challenge. The constant turnover of synovial fluid results in short residence time of administered drugs in the joint space and the dense negatively charged matrix of cartilage hinders their diffusive transport. Drugs are, therefore, unable to reach their cell and matrix targets in sufficient doses, and fail to elicit relevant biological response, which has led to unsuccessful clinical trials. The high negative fixed charge density (FCD) of cartilage, however, can be used to convert cartilage from a barrier to drug entry into a depot by making drugs positively charged. Here we design cartilage penetrating and binding cationic peptide carriers (CPCs) with varying net charge, spatial distribution and hydrophobicity to deliver large-sized therapeutics and investigate their electro-diffusive transport in healthy and arthritic cartilage. We showed that CPC uptake increased with increasing net charge up to +14 but dropped as charge increased further due to stronger binding interactions that hindered CPC penetrability and uptake showing that weak-reversible binding is key to enable their penetration through full tissue thickness. Even after 90% GAG depletion, while CPC +14 uptake reduced by over 50% but still had a significantly high value of 148x showing that intra-tissue longrange charge-based binding is further stabilized by short-range H-bond and hydrophobic interactions. The work presents an approach for rational design of cationic carriers based on tissue FCD and properties of macromolecules to be delivered. These design rules can be extended to drug delivery for other avascular, negatively charged tissues.
Here we describe methods for synthesizing cationic multiarm Avidin (mAv) nanoconstruct that has a... more Here we describe methods for synthesizing cationic multiarm Avidin (mAv) nanoconstruct that has a wide range of applications in drug delivery and imaging for a variety of negatively charged tissues. The multiarm structure provides multiple sites for covalent conjugation of drugs. We use avidin-biotin reaction that gives the flexibility for conjugating any desired biotinylated drug to mAv by simple mixing at room temperature. We also describe methods to control hydrolysis rates of ester linkers to enable sustained (and tunable) drug release rates in therapeutic doses.
Strategies to direct the differentiation of endogenous bone marrow derived mesenchymal stem cells... more Strategies to direct the differentiation of endogenous bone marrow derived mesenchymal stem cells (BMSCs) in vivo following recruitment to the injured site are critical to realizing the potential of stem cell-based therapies. But the differentiation efficiency of BMSCs remains limited without direction. Here we demonstrated a novel strategy to promote neuronal differentiation of BMSCs using cross-linked polyethylenimine (PEI) grafted graphene oxide (GO) as the enzyme responsive vector for delivering active genes to BMSCs. In vivo, a core-shell microfiber arrayed hydrogel with a chemokine (SDF-1α) and the cross-linked GO-PEI/pDNAs-bFGF microparticles incorporated into the shell and core, respectively, were constructed. The arrayed hydrogel was shown to recruit and stimulate the neural-like differentiation of BMSCs effectively by delivering the CXCL12 and GO-PEI/pDNAs-bFGF in a self-controlled manner. With this strategy, both in vitro and in vivo neuronal differentiation of BMSCs with...
High-purity milk exosomes were engineered with surface PEGylation and siRNA encapsulation for enh... more High-purity milk exosomes were engineered with surface PEGylation and siRNA encapsulation for enhanced oral drug delivery.
European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V, 2016
Asiaticoside is a natural compound possessing diverse pharmacological effects with great potentia... more Asiaticoside is a natural compound possessing diverse pharmacological effects with great potential for clinical use. However, the low solubility and oil-water partition coefficient of asiaticoside lead to reduced effect and limited application. This study aims to construct a porous microsphere for the sustained release of asiaticoside to improve its absorption and enhance the therapeutic effects. Parameters of the formulations, including the drug to polymer ratio, solvent amounts of the inner and external phases, the stirring speed for preparation, and the drug entrapment efficiency were investigated and optimized. Particle size, morphology, pores structure, and Fourier transform infrared spectrum of the microsphere were characterized. The release kinetics and cellular uptake profiles of the asiaticoside-microspheres were examined. The therapeutic effects of asiaticoside-microspheres on wound healing and skin appendages regeneration were investigated in vitro & in vivo. Results show...
Melanin is the one of most important pigments for skin color in mammals. Excessive biosynthesis o... more Melanin is the one of most important pigments for skin color in mammals. Excessive biosynthesis of melanin induces various pigment disorders. Much effort has been made to develop regulators to minimize skin pigmentation abnormalities. However, only a few of them are used, primarily because of safety concerns and low efficiency. In this study, we aimed to construct a novel nanosphere-gel for sequential delivery of salidroside and paeonol, to investigate the synergistic effects of these drugs in anti-melanogenesis, and to decrease their potential for toxicity in high dosage. Nanospheres were prepared and characterized for their particle size, polydispersity index, zeta potential, and morphological properties. The optimized nanospheres were incorporated in carbomer hydrogel with both paeonol and salidroside entrapped to form a dual drug-releasing nanosphere-gel. With this nanosphere-gel, rapid release of salidroside from the hydrogel followed by sustained release of paeonol from the na...
Most nonviral gene delivery systems are not efficient enough to manipulate the difficult-to-trans... more Most nonviral gene delivery systems are not efficient enough to manipulate the difficult-to-transfect cell types, including non-dividing, primary, neuronal or stem cells, due to a lack of an intrinsic capacity to enter the membrane and nucleus, release its DNA payload, and activate transcription. Noble metal nanoclusters have emerged as a fascinating area of widespread interest in nanomaterials. Herein, we report the synthesis of the TAT peptide conjugated cationic noble metal nanoparticles (metal NPs@PEI-TAT) as highly efficient carriers for gene delivery to stem cells. The metal NPs@PEI-TAT integrate the advantages of metal NPs and peptides: the presence of metal NPs can effectively decrease the cytotoxicity of cationic molecules, making it possible to apply them in biological systems, while the cell penetrating peptides are essential for enhanced cellular and nucleus entry to achieve high transfection efficiency. Our studies provide strong evidence that the metal NPs@PEI-TAT can be engineered as gene delivery agents for stem cells and subsequently enhance their directed differentiation for biomedical application.
Gold nanoparticles (AuNPs) have emerged as attractive non-viral gene vectors. However their appli... more Gold nanoparticles (AuNPs) have emerged as attractive non-viral gene vectors. However their application in regenerative medicine is still limited partially due to a lack of an intrinsic capacity to transfect difficult-to-transfect cells such as primary cells or stem cells. In current study, we report the synthesis of antimicrobial peptide conjugated cationic AuNPs (AuNPs@PEP) as highly efficient carriers for gene delivery to stem cells with antibacterial ability. The AuNPs@PEP integrate the advantages of cationic AuNPs and antibacterial peptides: the presence of cationic AuNPs can effectively condense DNA and the antimicrobial peptides are essential for the cellular & nucleus entry enhancement to achieve high transfection efficiency and antibacterial ability. As a result, antimicrobial peptides conjugated AuNPs significantly promoted the gene transfection efficiency in rat mesenchymal stem cells than pristine AuNPs, with a similar extent to those expressed by TAT (a well-known cell-...
Systemic administration of chemotherapeutic agents can cause indiscriminate drug distribution and... more Systemic administration of chemotherapeutic agents can cause indiscriminate drug distribution and severe toxicity. Until now, encapsulation and targeting of drugs have typically relied on synthetic vehicles, which cannot minimize the clearance by the renal system and may also increase the risk of chemical side effects. Cell membrane capsules (CMCs) provide a generic and far more natural approach to the challenges of drug encapsulation and delivery in vivo. Here aptamer AS1411, which can recognize and bind overexpressed nucleolin on a cancer cell membrane, was chemically conjugated onto CMCs. As a result, AS1411 modified CMCs showed enhanced ingestion in certain cancer cells in vitro and accumulation in mouse cancer xenografts in vivo. Chemotherapeutics and contrast agents with therapeutically significant concentrations can be packaged into CMCs by reversible permeating their plasma membranes. The systematic administration of cancer targeting CMCs loaded with doxorubicin hydrochlorid...
Repair of deep wounds by cell transplantation strongly depends on angiogenesis and on the regener... more Repair of deep wounds by cell transplantation strongly depends on angiogenesis and on the regeneration of skin and appendages. In this study, plasmid DNA encoding vascular endothelial growth factor-165 (VEGF-165) was transduced into bone-marrow mesenchymal stem cells (MSCs) using a nonviral vector, β-cyclodextrin-linked polyethylenimine, to enhance angiogenic capacity. The effects of MSCs administered by intradermal injection or transplantation on wound closure were compared in a full-thickness excision wound model. The results showed that the MSC-seeded sponge had significantly stronger acceleration in wound closure than the MSC injection. The effects on wound repair and regeneration of transplanted MSCs and pDNA-VEGF1 65-transfected MSCs (TMSCs) with gelatin/β-tricalcium phosphate scaffold were also investigated. Compared with MSC transplantation, TMSC transplantation showed higher efficacy in stimulating wound closure, promoting dermal collagen synthesis and regulating the deposition of newly formed collagen. In addition, the angiogenic capacity of the TMSCs was higher than that of the MSCs. The results indicate that the nonviral genetic engineering of the MSCs is a promising strategy to enhance the angiogenic capacity of MSCs for wound repair and angiogenesis. Functional gene-activated MSCs may be used as cost-effective and accessible seed cells for skin tissue engineering and as novel carriers for wound gene therapy.
Drug delivery to avascular, negatively charged tissues like cartilage remains a challenge. The co... more Drug delivery to avascular, negatively charged tissues like cartilage remains a challenge. The constant turnover of synovial fluid results in short residence time of administered drugs in the joint space and the dense negatively charged matrix of cartilage hinders their diffusive transport. Drugs are, therefore, unable to reach their cell and matrix targets in sufficient doses, and fail to elicit relevant biological response, which has led to unsuccessful clinical trials. The high negative fixed charge density (FCD) of cartilage, however, can be used to convert cartilage from a barrier to drug entry into a depot by making drugs positively charged. Here we design cartilage penetrating and binding cationic peptide carriers (CPCs) with varying net charge, spatial distribution and hydrophobicity to deliver large-sized therapeutics and investigate their electro-diffusive transport in healthy and arthritic cartilage. We showed that CPC uptake increased with increasing net charge up to +14 but dropped as charge increased further due to stronger binding interactions that hindered CPC penetrability and uptake showing that weak-reversible binding is key to enable their penetration through full tissue thickness. Even after 90% GAG depletion, while CPC +14 uptake reduced by over 50% but still had a significantly high value of 148x showing that intra-tissue longrange charge-based binding is further stabilized by short-range H-bond and hydrophobic interactions. The work presents an approach for rational design of cationic carriers based on tissue FCD and properties of macromolecules to be delivered. These design rules can be extended to drug delivery for other avascular, negatively charged tissues.
Here we describe methods for synthesizing cationic multiarm Avidin (mAv) nanoconstruct that has a... more Here we describe methods for synthesizing cationic multiarm Avidin (mAv) nanoconstruct that has a wide range of applications in drug delivery and imaging for a variety of negatively charged tissues. The multiarm structure provides multiple sites for covalent conjugation of drugs. We use avidin-biotin reaction that gives the flexibility for conjugating any desired biotinylated drug to mAv by simple mixing at room temperature. We also describe methods to control hydrolysis rates of ester linkers to enable sustained (and tunable) drug release rates in therapeutic doses.
Strategies to direct the differentiation of endogenous bone marrow derived mesenchymal stem cells... more Strategies to direct the differentiation of endogenous bone marrow derived mesenchymal stem cells (BMSCs) in vivo following recruitment to the injured site are critical to realizing the potential of stem cell-based therapies. But the differentiation efficiency of BMSCs remains limited without direction. Here we demonstrated a novel strategy to promote neuronal differentiation of BMSCs using cross-linked polyethylenimine (PEI) grafted graphene oxide (GO) as the enzyme responsive vector for delivering active genes to BMSCs. In vivo, a core-shell microfiber arrayed hydrogel with a chemokine (SDF-1α) and the cross-linked GO-PEI/pDNAs-bFGF microparticles incorporated into the shell and core, respectively, were constructed. The arrayed hydrogel was shown to recruit and stimulate the neural-like differentiation of BMSCs effectively by delivering the CXCL12 and GO-PEI/pDNAs-bFGF in a self-controlled manner. With this strategy, both in vitro and in vivo neuronal differentiation of BMSCs with...
High-purity milk exosomes were engineered with surface PEGylation and siRNA encapsulation for enh... more High-purity milk exosomes were engineered with surface PEGylation and siRNA encapsulation for enhanced oral drug delivery.
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Papers by Chenzhen Zhang