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2019 Volume 50 Issue 6
2019, 50(6):
Abstract:
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2019, 50(6): 1-1
Abstract:
生物医用高分子是多学科交叉的研究方向，致力于满足生物医用领域的需求，服务于全方位和全周期保障人民的健康. 一方面，我们将高分子科学的理论研究与实际应用相结合，发展医用高分子材料，拓宽高分子科学的外延；另一方面，针对生物和医学技术进步不断提出的新要求，改进高分子合成和制备方法，丰富和发展高分子科学内涵.
前言的详细内容请下载PDF文件.
2019, 50(6): 543-552
doi: 10.11777/j.issn1000-3304.2019.19036
Abstract:
Tumor-targeting drug delivery systems based on poly(ethylene glycol)-poly(amino acid) carriers have great potential in reducing the side effects of anticancer drugs, increasing the therapeutic index, and enhancing the druggability of drug candidates. In this work, recent progresses of our group in the tumor-targeting drug delivery systems with poly(L-glutamic acid)-graft-poly(ethylene glycol) (PLG-g-mPEG) as carrier, are reviewed. The influence of polymer structure on the behavior of nanomedicine in vivo is discussed. Several parameters, including PLG molecular weight, mPEG/PLG weight ratio, mPEG chain length and drug loading content, have a significant influence on the plasma pharmacokinetics of the cisplatin-loaded PLG-g-mPEG nanoparticles (CDDP-NPs). The blood circulation time of the nanoparticles is prolonged with increases in PLG molecular weight, mPEG/PLG weight ratio, mPEG chain length and cisplatin loading content. Cooperative treatment concepts, such as " periphery and center” and " coagulation targeting”, are proposed. By coadministering a vascular disrupting agent (VDA) CA4P and CDDP-NPs, the CDDP-NPs mainly locates at the tumor periphery and leaves most of cancer cells at tumor center viable, the CA4P can make up defect of CDDP-NPs and efficiently kill cancer cells in tumor central regions. The " coagulation targeting” delivery platform comprises a coagulation-inducing agent and coagulation-targeted polymeric nanoparticles. As a typical VDA, DMXAA can create a unique artificial coagulation environment with additional binding sites in a solid tumor by locally activating a coagulation cascade. Coagulation-targeted cisplatin-loaded nanoparticles can selectively accumulate in the solid tumor by homing to the VDA-induced artificial coagulation environment through transglutamination. We discover that the low permeability of nanomedicine in solid tumors can significantly improve the targeting to tumor blood vessels and tumor inhibition ability of VDAs. This provides a new idea for enhancing the therapeutic effect of VDAs in tumor treatment. A powerful combinational strategy is created with nanomedicine of VDAs plus hypoxia-activated prodrugs (HAPs) for the treatment of solid tumors. The nanomedicine of VDAs can selectively enhance tumor hypoxia and boost a typical HAP tirapazamine therapy against metastatic 4T1 breast tumors.
Tumor-targeting drug delivery systems based on poly(ethylene glycol)-poly(amino acid) carriers have great potential in reducing the side effects of anticancer drugs, increasing the therapeutic index, and enhancing the druggability of drug candidates. In this work, recent progresses of our group in the tumor-targeting drug delivery systems with poly(L-glutamic acid)-graft-poly(ethylene glycol) (PLG-g-mPEG) as carrier, are reviewed. The influence of polymer structure on the behavior of nanomedicine in vivo is discussed. Several parameters, including PLG molecular weight, mPEG/PLG weight ratio, mPEG chain length and drug loading content, have a significant influence on the plasma pharmacokinetics of the cisplatin-loaded PLG-g-mPEG nanoparticles (CDDP-NPs). The blood circulation time of the nanoparticles is prolonged with increases in PLG molecular weight, mPEG/PLG weight ratio, mPEG chain length and cisplatin loading content. Cooperative treatment concepts, such as " periphery and center” and " coagulation targeting”, are proposed. By coadministering a vascular disrupting agent (VDA) CA4P and CDDP-NPs, the CDDP-NPs mainly locates at the tumor periphery and leaves most of cancer cells at tumor center viable, the CA4P can make up defect of CDDP-NPs and efficiently kill cancer cells in tumor central regions. The " coagulation targeting” delivery platform comprises a coagulation-inducing agent and coagulation-targeted polymeric nanoparticles. As a typical VDA, DMXAA can create a unique artificial coagulation environment with additional binding sites in a solid tumor by locally activating a coagulation cascade. Coagulation-targeted cisplatin-loaded nanoparticles can selectively accumulate in the solid tumor by homing to the VDA-induced artificial coagulation environment through transglutamination. We discover that the low permeability of nanomedicine in solid tumors can significantly improve the targeting to tumor blood vessels and tumor inhibition ability of VDAs. This provides a new idea for enhancing the therapeutic effect of VDAs in tumor treatment. A powerful combinational strategy is created with nanomedicine of VDAs plus hypoxia-activated prodrugs (HAPs) for the treatment of solid tumors. The nanomedicine of VDAs can selectively enhance tumor hypoxia and boost a typical HAP tirapazamine therapy against metastatic 4T1 breast tumors.
2019, 50(6): 553-566
doi: 10.11777/j.issn1000-3304.2019.19031
Abstract:
Polymersomes, also referred to as polymer vesicles, are self-assembled from amphiphilic synthetic polymers, representing a type of hollow nanostructures containing aqueous lumens enclosed by bilayer membranes. This unique hollow and compartmentalized structure has been extensively used in the fabrication of artificial cells, drug carriers, and nanoreactors. Albeit more stable than liposomes, polymersomes exhibit relatively low permeability toward macromolecules, small molecules, ions, and even water molecules. This drawback remarkably hampers the biomedical applications of polymersomes. Thus, it is of crucial importance to regulate the permeability of polymersomes while maintaining structural integrity. Although a number of methods have been proposed to enhance the permeability of polymersomes such as the fabrication of stimuli-responsive polymersomes and the introduction of channel proteins, these procedures suffer from either tedious protocols or disruption of the vesicular structures. In this feature article, we summarize our recent achievements in the (ir)reversible regulation of the permeability of polymersomes. First, we conceived a new concept, termed as " traceless” cross-linking, to synergistically stabilize and permeate polymersomes. This concept originates from photoresponsive polymersomes, in which we found that the photo-caged primary amines underwent inter/intrachain amidation reactions other than protonation reactions within the initially hydrophobic bilayer membranes. Moreover, this robust strategy can be readily extended to other bio-related triggering events such as enzyme and redox. Notably, " traceless” cross-linking generally led to irreversible chemical cross-linking of polymersomes. Thus, in the following section, we showcased the representative examples in reversible modulation the permeability of polymersomes by taking advantage of cooperative noncovalent interactions. These new methodologies successfully resolve the dilemma of the structural stability and bilayer permeability of polymersomes and can be used for the fabrication of smart nanocarriers and nanoreactors. Finally, we give a brief summary and outlook of this emerging field.
Polymersomes, also referred to as polymer vesicles, are self-assembled from amphiphilic synthetic polymers, representing a type of hollow nanostructures containing aqueous lumens enclosed by bilayer membranes. This unique hollow and compartmentalized structure has been extensively used in the fabrication of artificial cells, drug carriers, and nanoreactors. Albeit more stable than liposomes, polymersomes exhibit relatively low permeability toward macromolecules, small molecules, ions, and even water molecules. This drawback remarkably hampers the biomedical applications of polymersomes. Thus, it is of crucial importance to regulate the permeability of polymersomes while maintaining structural integrity. Although a number of methods have been proposed to enhance the permeability of polymersomes such as the fabrication of stimuli-responsive polymersomes and the introduction of channel proteins, these procedures suffer from either tedious protocols or disruption of the vesicular structures. In this feature article, we summarize our recent achievements in the (ir)reversible regulation of the permeability of polymersomes. First, we conceived a new concept, termed as " traceless” cross-linking, to synergistically stabilize and permeate polymersomes. This concept originates from photoresponsive polymersomes, in which we found that the photo-caged primary amines underwent inter/intrachain amidation reactions other than protonation reactions within the initially hydrophobic bilayer membranes. Moreover, this robust strategy can be readily extended to other bio-related triggering events such as enzyme and redox. Notably, " traceless” cross-linking generally led to irreversible chemical cross-linking of polymersomes. Thus, in the following section, we showcased the representative examples in reversible modulation the permeability of polymersomes by taking advantage of cooperative noncovalent interactions. These new methodologies successfully resolve the dilemma of the structural stability and bilayer permeability of polymersomes and can be used for the fabrication of smart nanocarriers and nanoreactors. Finally, we give a brief summary and outlook of this emerging field.
2019, 50(6): 567-574
doi: 10.11777/j.issn1000-3304.2019.18268
Abstract:
Over the past decades, nanotechnology has been intensively investigated for application in drug delivery, cancer treatment, and cancer diagnostics. Treatment with cancer nanomedicines have shown many benefits in improving clinical translation potential and drug biodistribution, reducing side effects and improving the life quality of patients, compared with that by small-molecule anticancer therapeutics. However, a series of complex biological barriers, including the blood barriers, tumor microenvironment barriers, intratumor cell barriers considerably prevent a nanomedicine from reaching its targets in a sufficient concentration and thus severely limit its therapeutic benefits. A feasible strategy is to formulate the nanocarriers in response to microenvironment and to tune their properties to adapt to each individual environment for robust and effective delivery. In this review, we systemically summarize the principles of nanoparticle design for overcoming multiple biological barriers in drug delivery, and conclude the ideal properties of nanomedicine and its biological effects in the microenvironment of each stage, such as blood, extracellular region and intratumor cell in drug delivery. This can guide the development of intelligent nanomedicine which can overcome the drug delivery barriers by making subtle response to the changes of physiological signal. In this review, we highlight some typical strategies we developed in recent 10 years, especially the nanocarriers response to the acidic extracellular environment, to improve the delivery efficiency after systemic administration, including surface charge reversal, surface PEG detachment, particle size transition and ligand reactivation. Finally, the opportunities and challenges in tumor responsive nanomedicines are also disscussed.
Over the past decades, nanotechnology has been intensively investigated for application in drug delivery, cancer treatment, and cancer diagnostics. Treatment with cancer nanomedicines have shown many benefits in improving clinical translation potential and drug biodistribution, reducing side effects and improving the life quality of patients, compared with that by small-molecule anticancer therapeutics. However, a series of complex biological barriers, including the blood barriers, tumor microenvironment barriers, intratumor cell barriers considerably prevent a nanomedicine from reaching its targets in a sufficient concentration and thus severely limit its therapeutic benefits. A feasible strategy is to formulate the nanocarriers in response to microenvironment and to tune their properties to adapt to each individual environment for robust and effective delivery. In this review, we systemically summarize the principles of nanoparticle design for overcoming multiple biological barriers in drug delivery, and conclude the ideal properties of nanomedicine and its biological effects in the microenvironment of each stage, such as blood, extracellular region and intratumor cell in drug delivery. This can guide the development of intelligent nanomedicine which can overcome the drug delivery barriers by making subtle response to the changes of physiological signal. In this review, we highlight some typical strategies we developed in recent 10 years, especially the nanocarriers response to the acidic extracellular environment, to improve the delivery efficiency after systemic administration, including surface charge reversal, surface PEG detachment, particle size transition and ligand reactivation. Finally, the opportunities and challenges in tumor responsive nanomedicines are also disscussed.
2019, 50(6): 575-587
doi: 10.11777/j.issn1000-3304.2019.18276
Abstract:
A hallmark event of neurodegenerative diseases (NDs) is the misfolding, aggregation and fibrillation of related proteins, namely amyloidosis. For example, amyloid-β (Aβ) and Tau, α-synuclein (α-syn), superoxide dismutase 1 (SOD1) and huntingtin exon 1 (HTTexon1) are tightly linked to Alzheimer’s Disease (AD), Parkinson Disease (PD), Amyotrophic Lateral Sclerosis (ALS) and Huntington ’s Disease (HD), respectively. Plasma membrane plays a crucial role in the pathological processes of NDs, including the production, intracellular diffusion, intercellular transmission, endocytosis and clearance of NDs proteins and the resulting aggregates. Therefore, the interactions between NDs proteins and membrane interfaces significantly influence the protein fibrillation and NDs pathogenesis. Properties of membrane interfaces including amphiphilicity and charge density can influence the adsorption of proteins onto membranes and thus the protein folding and aggregation. As the basic chemical property of plasma membranes, chirality can determine key biophysical interactions. The alternation of molecule chirality can cause entirely different biophysical interactions and thus the biofunctions. From this biomimetic perspective, extensive works have demonstrated that the chirality of interfaces can significantly affect protein-surface interactions and thus the fibrillation processes. This brings us to reconsider the stereoselective interactions between NDs proteins and the chiral moieties on membrane interfaces and their impact during NDs pathogenesis. This review article is aimed to reveal the key role of membrane interfaces in protein fibrillation and discuss the impact of interfaces during NDs pathogenesis. The stereoselective protein-membrane interactions and their effects on protein fibrillation are elucidated from a molecular level. The designs of NDs drugs based on chiral interactions are also discussed. These specific aims will deepen our mechanistic insights into how interfaces affect NDs pathogenesis and facilitate the discovery of effective drugs for preventing protein fibrillation and eventually the cure of NDs.
A hallmark event of neurodegenerative diseases (NDs) is the misfolding, aggregation and fibrillation of related proteins, namely amyloidosis. For example, amyloid-β (Aβ) and Tau, α-synuclein (α-syn), superoxide dismutase 1 (SOD1) and huntingtin exon 1 (HTTexon1) are tightly linked to Alzheimer’s Disease (AD), Parkinson Disease (PD), Amyotrophic Lateral Sclerosis (ALS) and Huntington ’s Disease (HD), respectively. Plasma membrane plays a crucial role in the pathological processes of NDs, including the production, intracellular diffusion, intercellular transmission, endocytosis and clearance of NDs proteins and the resulting aggregates. Therefore, the interactions between NDs proteins and membrane interfaces significantly influence the protein fibrillation and NDs pathogenesis. Properties of membrane interfaces including amphiphilicity and charge density can influence the adsorption of proteins onto membranes and thus the protein folding and aggregation. As the basic chemical property of plasma membranes, chirality can determine key biophysical interactions. The alternation of molecule chirality can cause entirely different biophysical interactions and thus the biofunctions. From this biomimetic perspective, extensive works have demonstrated that the chirality of interfaces can significantly affect protein-surface interactions and thus the fibrillation processes. This brings us to reconsider the stereoselective interactions between NDs proteins and the chiral moieties on membrane interfaces and their impact during NDs pathogenesis. This review article is aimed to reveal the key role of membrane interfaces in protein fibrillation and discuss the impact of interfaces during NDs pathogenesis. The stereoselective protein-membrane interactions and their effects on protein fibrillation are elucidated from a molecular level. The designs of NDs drugs based on chiral interactions are also discussed. These specific aims will deepen our mechanistic insights into how interfaces affect NDs pathogenesis and facilitate the discovery of effective drugs for preventing protein fibrillation and eventually the cure of NDs.
2019, 50(6): 588-601
doi: 10.11777/j.issn1000-3304.2019.19005
Abstract:
At present, cancer nanomedicine mainly focuses on mitigating adverse effects but fails to enhance the therapeutic efficacies of anticancer drugs. With the benchmark of the recent highly effective molecular targeted therapies and immunotherapies, rational design of next-generation cancer nanomedicine should aim at enhancing its therapeutic efficacy. From this point of view, this review first analyszs the typical cancer-drug-delivery process of an intravenously administered nanomedicine and concludes as a cascade of five steps, including circulation in the blood compartments, accumulation in the tumor, subsequent penetration deep into the tumor tissue to reach tumor cells, internalization into those cells, and finally intracellular drug release (CAPIR cascade for short). High efficiency of every step is critical for a nanomedicine to achieve a high overall delivery efficiency and thereby improve the whole therapeutic efficiency. Further analysis shows that to maximize its efficiency, the nanoproperties required in each step for a nanomedicine are different and even opposite in different steps, such as PEG, surface-charge, size, and stability dilemmas. To resolve these dilemmas and integrate all the required nanoproperties into one nanomedicine, stability, surface, and size nanoproperty transitions (3S transitions for short) are proposed. Stimulus-responsive polymers have been designed to realize the 3S transitions, including pH-, ROS-, redox-, enzyme-responsive, and so on. Smart nanomedicines possessing the 3S transitions are demonstrated. The challenges in designing high-performance cancer nanomedicines and their clinical translations are then discussed. Clinical translation is the ultimate goal of nanomedicine research. To design translational nanomedicines, the three key elements, 3S transition capability, material excipientability, and process scale-up ability (CES elements for short) must be considered. Our recent development of noncytotoxic with highly potent therapeutic polymers as a new type of molecular nanomedicine is summarized. Finally, by comparing viral vectors, a possible solution for multifunctional nanomedicines to realize their clinical translation is proposed.
At present, cancer nanomedicine mainly focuses on mitigating adverse effects but fails to enhance the therapeutic efficacies of anticancer drugs. With the benchmark of the recent highly effective molecular targeted therapies and immunotherapies, rational design of next-generation cancer nanomedicine should aim at enhancing its therapeutic efficacy. From this point of view, this review first analyszs the typical cancer-drug-delivery process of an intravenously administered nanomedicine and concludes as a cascade of five steps, including circulation in the blood compartments, accumulation in the tumor, subsequent penetration deep into the tumor tissue to reach tumor cells, internalization into those cells, and finally intracellular drug release (CAPIR cascade for short). High efficiency of every step is critical for a nanomedicine to achieve a high overall delivery efficiency and thereby improve the whole therapeutic efficiency. Further analysis shows that to maximize its efficiency, the nanoproperties required in each step for a nanomedicine are different and even opposite in different steps, such as PEG, surface-charge, size, and stability dilemmas. To resolve these dilemmas and integrate all the required nanoproperties into one nanomedicine, stability, surface, and size nanoproperty transitions (3S transitions for short) are proposed. Stimulus-responsive polymers have been designed to realize the 3S transitions, including pH-, ROS-, redox-, enzyme-responsive, and so on. Smart nanomedicines possessing the 3S transitions are demonstrated. The challenges in designing high-performance cancer nanomedicines and their clinical translations are then discussed. Clinical translation is the ultimate goal of nanomedicine research. To design translational nanomedicines, the three key elements, 3S transition capability, material excipientability, and process scale-up ability (CES elements for short) must be considered. Our recent development of noncytotoxic with highly potent therapeutic polymers as a new type of molecular nanomedicine is summarized. Finally, by comparing viral vectors, a possible solution for multifunctional nanomedicines to realize their clinical translation is proposed.
2019, 50(6): 602-612
doi: 10.11777/j.issn1000-3304.2019.18260
Abstract:
Gene therapy is widely concerned as an excellent treatment for cancer. One of the most important things in gene therapy is to construct gene delivery systems with good biodegradability, biocompatibility, and gene delivery capability. Biodegradable non-viral gene vectors based on different microenvironments between cancer cells and normal cells have been paid more attention. In this work, the reduction-responsive branched polylysine (SS-HP) with disulfide bonds was synthesized via a one-pot ring-opening reaction. To make a comparison, the branched polylysine without disulfide bonds (CC-HP) was synthesized by the same method. All the SS-HP/pDNA and CC-HP/pDNA complexes with various weight ratios were prepared by mixing polycation-based solution and pDNA solution completely, and stood for 30 min. The particle size and zeta potential of SS-HP/pDNA and CC-HP/pDNA were measured by dynamic light scattering (DLS). The degradability of polyplexes in reductive environment was visualized by agarose gel electrophoresis and atomic force microscopy (AFM). The in vitro transfection efficiencies and cell viability of SS-HP and CC-HP were evaluated in C6 and HepG2 cell lines using luciferase reporter gene, green fluorescence protein gene, and MTT assay. The concentration of reductive glutathione (GSH) is higher in some cancer cells than that in normal cells. SS-HP showed high gene transfection efficiency in vitro due to the breakdown of reduction-responsive disulfide bonds. Moreover, SS-HP exhibited low cytotoxicity due to the good biodegradability of SS-HP and plenty of hydroxy groups induced by ring-opening reactions. KillerRed protein is a red fluorescence protein which could produce reactive oxygen species (ROS) upon the induction of visible light. From in vitro antitumor assays, the plasmid pKillerRed (pKR) delivered by SS-HP was expressed in C6 cells. KillerRed protein expressed in C6 cells could contribute to the cell apoptosis via photodynamic therapy (PDT). This study provides a novel approach for designing the next-generation gene delivery systems.
Gene therapy is widely concerned as an excellent treatment for cancer. One of the most important things in gene therapy is to construct gene delivery systems with good biodegradability, biocompatibility, and gene delivery capability. Biodegradable non-viral gene vectors based on different microenvironments between cancer cells and normal cells have been paid more attention. In this work, the reduction-responsive branched polylysine (SS-HP) with disulfide bonds was synthesized via a one-pot ring-opening reaction. To make a comparison, the branched polylysine without disulfide bonds (CC-HP) was synthesized by the same method. All the SS-HP/pDNA and CC-HP/pDNA complexes with various weight ratios were prepared by mixing polycation-based solution and pDNA solution completely, and stood for 30 min. The particle size and zeta potential of SS-HP/pDNA and CC-HP/pDNA were measured by dynamic light scattering (DLS). The degradability of polyplexes in reductive environment was visualized by agarose gel electrophoresis and atomic force microscopy (AFM). The in vitro transfection efficiencies and cell viability of SS-HP and CC-HP were evaluated in C6 and HepG2 cell lines using luciferase reporter gene, green fluorescence protein gene, and MTT assay. The concentration of reductive glutathione (GSH) is higher in some cancer cells than that in normal cells. SS-HP showed high gene transfection efficiency in vitro due to the breakdown of reduction-responsive disulfide bonds. Moreover, SS-HP exhibited low cytotoxicity due to the good biodegradability of SS-HP and plenty of hydroxy groups induced by ring-opening reactions. KillerRed protein is a red fluorescence protein which could produce reactive oxygen species (ROS) upon the induction of visible light. From in vitro antitumor assays, the plasmid pKillerRed (pKR) delivered by SS-HP was expressed in C6 cells. KillerRed protein expressed in C6 cells could contribute to the cell apoptosis via photodynamic therapy (PDT). This study provides a novel approach for designing the next-generation gene delivery systems.
2019, 50(6): 613-622
doi: 10.11777/j.issn1000-3304.2019.18270
Abstract:
In this work, a very simple method for preparing a mechanically strong, highly adhesive, and biocompatible hydrogel was reported. The aqueous solution of N-acryloyl-2-aminoacetic acid (ACG) and nano-bioactive glass (BG) was mixed, followed by UV light irradiation to initiate polymerization for preparing the PACG-BG nano-hybrid hydrogels rapidly. The intermolecular hydrogen bonds from PACG chains, coordination between PACG-end carboxyls and metal ions of BG, as well as PACG-BG physical interaction collectively formed multiple physical crosslinks, were contributed to the increased mechanical strengths. The studies of PACG-BG hydrogels demonstrated that tunable mechanical properties, adhesion abilities, and room temperature self-healing ability could be adjusted by changing the contents of ACG and BG. The adhesion strengths of the hydrogels were tested by tension loading in lap-shear mode. The results indicated that at 25 wt% ACG and 6 wt% BG (relative to ACG), the hydrogels could achieve a balance between surface adhesion and cohesion energies; in this case, the maximum instant adhesion strengths toward pig’s skin, ion sheet, and ceramic were measured to be 120, 142, and 125 kPa, respectively, and the adhesion strengths of hydrogels toward pig skin, ion sheet, and ceramics was presumably originated from the enrichment of PACG chains to the substrates facilitated by the BG nanoparticles. This allowed more carboxyl groups on the hydrogel surface to form hydrogen bonds, ionic coordination, and dipole interactions with the adherends, consequently leading to the enhanced adhesion to these materials. Intriguingly, the highest tensile strength of the hydrogel was as high as 0.9 MPa, fracture energy could reach 1500 J m−2, and self-healing efficiency could reach 100% after 12 h at room temperature without manual intervention. The outcomes of in vivo implantation showed that the hydrogel possessed better biocompatibility. In light of its robust adhesion to biological soft tissues, the hydrogel was used for in vitro adhering and mending the animal’s gastric perforation. The results revealed that the hydrogel could adhere firmly to the perforated stomach, thus preventing leakage of gastric fluid. This novel organic-inorganic hybrid hydrogel holds promising potential as a biomedical first-aid bandage.
In this work, a very simple method for preparing a mechanically strong, highly adhesive, and biocompatible hydrogel was reported. The aqueous solution of N-acryloyl-2-aminoacetic acid (ACG) and nano-bioactive glass (BG) was mixed, followed by UV light irradiation to initiate polymerization for preparing the PACG-BG nano-hybrid hydrogels rapidly. The intermolecular hydrogen bonds from PACG chains, coordination between PACG-end carboxyls and metal ions of BG, as well as PACG-BG physical interaction collectively formed multiple physical crosslinks, were contributed to the increased mechanical strengths. The studies of PACG-BG hydrogels demonstrated that tunable mechanical properties, adhesion abilities, and room temperature self-healing ability could be adjusted by changing the contents of ACG and BG. The adhesion strengths of the hydrogels were tested by tension loading in lap-shear mode. The results indicated that at 25 wt% ACG and 6 wt% BG (relative to ACG), the hydrogels could achieve a balance between surface adhesion and cohesion energies; in this case, the maximum instant adhesion strengths toward pig’s skin, ion sheet, and ceramic were measured to be 120, 142, and 125 kPa, respectively, and the adhesion strengths of hydrogels toward pig skin, ion sheet, and ceramics was presumably originated from the enrichment of PACG chains to the substrates facilitated by the BG nanoparticles. This allowed more carboxyl groups on the hydrogel surface to form hydrogen bonds, ionic coordination, and dipole interactions with the adherends, consequently leading to the enhanced adhesion to these materials. Intriguingly, the highest tensile strength of the hydrogel was as high as 0.9 MPa, fracture energy could reach 1500 J m−2, and self-healing efficiency could reach 100% after 12 h at room temperature without manual intervention. The outcomes of in vivo implantation showed that the hydrogel possessed better biocompatibility. In light of its robust adhesion to biological soft tissues, the hydrogel was used for in vitro adhering and mending the animal’s gastric perforation. The results revealed that the hydrogel could adhere firmly to the perforated stomach, thus preventing leakage of gastric fluid. This novel organic-inorganic hybrid hydrogel holds promising potential as a biomedical first-aid bandage.
2019, 50(6): 623-632
doi: 10.11777/j.issn1000-3304.2019.18275
Abstract:
A novel type of unsaturated polyurethanes (PPFU-SS) containing disulfide bonds was synthesized by using poly(propylene fumarate) as the soft segment and dimethyl L-cystinate dihydrochloride as the chain extender. In order to improve the mechanical properties, polycaprolactone diol (PCL) was copolymerized as the soft segment as well to obtain the novel unsaturated copolymerized polyurethanes (PPFU-CO-SS). Moreover, unsaturated polyurethane (PPFU-Lys) without disulfide bonds was synthesized and used as the control group. The chemical structures of PPFU-SS, PPFU-Lys, and PPFU-CO-SS were characterized by 1H-NMR, IR, and Raman spectroscopy, revealing that there were many carbon-carbon double bonds and disulfide bonds in PPFU-SS and PPFU-CO-SS. The thermal properties of these three types of PPFU materials were characterized by DSC and TGA, which demonstrated their good thermal stability below 150 °C. The mechanical properties of these PPFUs were analyzed by universal mechanical testing, showing that the tensile strength of PPFU-CO-SS polymer was the highest with a value of 0.8 MPa. Therefore, the copolymerization with PCL has successfully improved the mechanical property of the novel unsaturated polyurethanes. The degradation of reduction-responsive PPFU-SS and PPFU-CO-SS was significantly accelerated in glutathione solution compared with that in phosphate buffered saline, whereas the degradation of PPFU-Lys had no obvious difference in these two types of solutions. Comparatively, PPFU-CO-SS showed a stronger hydrophobicity, water contact angle (93.5°) significantly larger than those of PPFU-SS (73.9°) and PPFU-Lys (74.4°). Culture of smooth muscle cells in vitro demonstrated that none of PPFU-SS, PPFU-Lys, and PPFU-CO-SS had obvious cytotoxicity. The cells cultured on the PPFU-SS and PPFU-Lys surfaces showed faster proliferation rates than those cultured on TCPS, whereas the cell proliferation rate on PPFU-CO-SS was comparable to that on TCPS. In conclusion, these results demonstrated that the reduction-responsive polyurethanes possess good mechanical strength, thermal stability, degradability in response to reductants, low cytotoxicity, and cell coMPatibility, and thus hold great potential in fields of drug delivery, tissue engineering, regenerative medicine, and therapy of diseases. Furthermore, the unsaturated and high active carbon-carbon double bonds can be used to graft desired molecules, enabling the diverse functionalization and thereby applications.
A novel type of unsaturated polyurethanes (PPFU-SS) containing disulfide bonds was synthesized by using poly(propylene fumarate) as the soft segment and dimethyl L-cystinate dihydrochloride as the chain extender. In order to improve the mechanical properties, polycaprolactone diol (PCL) was copolymerized as the soft segment as well to obtain the novel unsaturated copolymerized polyurethanes (PPFU-CO-SS). Moreover, unsaturated polyurethane (PPFU-Lys) without disulfide bonds was synthesized and used as the control group. The chemical structures of PPFU-SS, PPFU-Lys, and PPFU-CO-SS were characterized by 1H-NMR, IR, and Raman spectroscopy, revealing that there were many carbon-carbon double bonds and disulfide bonds in PPFU-SS and PPFU-CO-SS. The thermal properties of these three types of PPFU materials were characterized by DSC and TGA, which demonstrated their good thermal stability below 150 °C. The mechanical properties of these PPFUs were analyzed by universal mechanical testing, showing that the tensile strength of PPFU-CO-SS polymer was the highest with a value of 0.8 MPa. Therefore, the copolymerization with PCL has successfully improved the mechanical property of the novel unsaturated polyurethanes. The degradation of reduction-responsive PPFU-SS and PPFU-CO-SS was significantly accelerated in glutathione solution compared with that in phosphate buffered saline, whereas the degradation of PPFU-Lys had no obvious difference in these two types of solutions. Comparatively, PPFU-CO-SS showed a stronger hydrophobicity, water contact angle (93.5°) significantly larger than those of PPFU-SS (73.9°) and PPFU-Lys (74.4°). Culture of smooth muscle cells in vitro demonstrated that none of PPFU-SS, PPFU-Lys, and PPFU-CO-SS had obvious cytotoxicity. The cells cultured on the PPFU-SS and PPFU-Lys surfaces showed faster proliferation rates than those cultured on TCPS, whereas the cell proliferation rate on PPFU-CO-SS was comparable to that on TCPS. In conclusion, these results demonstrated that the reduction-responsive polyurethanes possess good mechanical strength, thermal stability, degradability in response to reductants, low cytotoxicity, and cell coMPatibility, and thus hold great potential in fields of drug delivery, tissue engineering, regenerative medicine, and therapy of diseases. Furthermore, the unsaturated and high active carbon-carbon double bonds can be used to graft desired molecules, enabling the diverse functionalization and thereby applications.
2019, 50(6): 633-641
doi: 10.11777/j.issn1000-3304.2019.19001
Abstract:
To make up for the inherent drawbacks (e.g. hydrophobicity, toxicity, and instability) of near-infrared Cypate dyes, as photothermal agents, stable hybrid nanoparticles (CBNPs) with small size were prepared from bovine serum albumin (BSA) and Cypate dyes under hydrothermal conditions. Free Cypate exhibited strong fluorescence whereas fluorescence quenching in CBNPs caused a sharp decrease in emission peak intensity, so the dye molecules were successfully assembled into protein nanoparticles. As-prepared CBNPs were characterized with dynamic light scattering (DLS) and transmission electron microscopy (TEM). The hydrodynamic diameter of CBNPs was around 25 – 40 nm with a low polydispersity index of 0.2, slightly higher than the measured values from TEM observation. BSA encapsulation could significantly improve the water solubility of Cypate dye and the stability of dye aqueous solutions. Besides, these nanoparticles showed good colloidal stability and biocompatibility. Photothermal experiments suggested that the protein nanoparticles had good photothermal performance and were able to generate enough heat under near-infrared laser irradiation. The photothermal conversion efficiency (η) of CBNPs under 808 nm laser irradiation reached up to 50%, which made them outperform the small molecules of neat Cypate dyes in terms of their photothermal conversion capabilities. Confocal laser scanning microscopy further revealed that the protein nanoparticles could be efficiently internalized by cancer cells in a time-dependent manner, which is very important for their therapeutic functions. Photothermal treatment toward human cervical carcinoma (HeLa) cells and human liver hepatocellular carcinoma (HepG2) cells under laser irradiation was extamined by MTT method, in which the protein nanoparticles showed an effective inhibition effect on tumor cell proliferation at the cellular level. Live/dead cell staining experiments conducted on HeLa cells also showed the same results intuitively. The dye-protein hybrid nanoparticles developed in this study as a novel nano-agent possess promising prospects in the field of tumor photothermal therapy.
To make up for the inherent drawbacks (e.g. hydrophobicity, toxicity, and instability) of near-infrared Cypate dyes, as photothermal agents, stable hybrid nanoparticles (CBNPs) with small size were prepared from bovine serum albumin (BSA) and Cypate dyes under hydrothermal conditions. Free Cypate exhibited strong fluorescence whereas fluorescence quenching in CBNPs caused a sharp decrease in emission peak intensity, so the dye molecules were successfully assembled into protein nanoparticles. As-prepared CBNPs were characterized with dynamic light scattering (DLS) and transmission electron microscopy (TEM). The hydrodynamic diameter of CBNPs was around 25 – 40 nm with a low polydispersity index of 0.2, slightly higher than the measured values from TEM observation. BSA encapsulation could significantly improve the water solubility of Cypate dye and the stability of dye aqueous solutions. Besides, these nanoparticles showed good colloidal stability and biocompatibility. Photothermal experiments suggested that the protein nanoparticles had good photothermal performance and were able to generate enough heat under near-infrared laser irradiation. The photothermal conversion efficiency (η) of CBNPs under 808 nm laser irradiation reached up to 50%, which made them outperform the small molecules of neat Cypate dyes in terms of their photothermal conversion capabilities. Confocal laser scanning microscopy further revealed that the protein nanoparticles could be efficiently internalized by cancer cells in a time-dependent manner, which is very important for their therapeutic functions. Photothermal treatment toward human cervical carcinoma (HeLa) cells and human liver hepatocellular carcinoma (HepG2) cells under laser irradiation was extamined by MTT method, in which the protein nanoparticles showed an effective inhibition effect on tumor cell proliferation at the cellular level. Live/dead cell staining experiments conducted on HeLa cells also showed the same results intuitively. The dye-protein hybrid nanoparticles developed in this study as a novel nano-agent possess promising prospects in the field of tumor photothermal therapy.
2019, 50(6): 642-652
doi: 10.11777/j.issn1000-3304.2019.19039
Abstract:
The " in vivo self-assembly” strategy was adopted to improve the efficacy of polymer-peptide conjugates (PPCs) in tumor destruction. Briefly, a pH-sensitive PPC was designed and synthesized, which could penetrate deep into the solid tumors as a single chain. Such single chain would subsequently respond to the mildly acidic environment inside the solid tumor and assemble into a ball, thereby acquiring higher internalization capacity and achieving an enhanced therapeutic function. The major work in this research is as follows. First, several β-thioester polymers were synthesized via a condensation polymerization, and two peptides were produced by solid-phase peptide synthesis. One of the peptides was modified with a pH-sensitive group, cis-aconitic anhydride, and then as-designed polymer-peptide conjugates were prepared by coupling the peptides with polymers through the Michael addition. The PPC products remained stable in a single stranded form under the neutral aqueous condition but aggregated at pH = 6.5. According to TEM observation, the size of PPCs in a pH = 6.5 solution increased from 17 nm to 88 nm in 12 h due to self-assembly, while no obvious size change was noticed under the pH = 7.4 condition. The PPCs modified with DBD group (PS-KFx-CAA-DBD) were dissolved in PBS at different pHs for FL measurement; the FL intensity was significantly increased at pH = 6.5 but barely changed at pH = 7.4, which verified acid-induced aggregation. The mechanism of peptide cytotoxicity is rooted in the destructive effect of α-helix structure on mitochondria membranes. Within 12 h, the content of α-helix structure increased slightly from 19.5% to 25.8% at pH = 7.4 but markedly to 58.9% at pH = 6.5. Based on the rapid hydrolysis of PPCs at pH = 6.5, the better recovery of α-helix structure implied a higher therapeutic activity. Therefore, this in vivo self-assembly strategy enables the peptide nanomaterials to penetrate deeper into the tumor cells and thus endows them with enhanced therapeutic efficacy.
The " in vivo self-assembly” strategy was adopted to improve the efficacy of polymer-peptide conjugates (PPCs) in tumor destruction. Briefly, a pH-sensitive PPC was designed and synthesized, which could penetrate deep into the solid tumors as a single chain. Such single chain would subsequently respond to the mildly acidic environment inside the solid tumor and assemble into a ball, thereby acquiring higher internalization capacity and achieving an enhanced therapeutic function. The major work in this research is as follows. First, several β-thioester polymers were synthesized via a condensation polymerization, and two peptides were produced by solid-phase peptide synthesis. One of the peptides was modified with a pH-sensitive group, cis-aconitic anhydride, and then as-designed polymer-peptide conjugates were prepared by coupling the peptides with polymers through the Michael addition. The PPC products remained stable in a single stranded form under the neutral aqueous condition but aggregated at pH = 6.5. According to TEM observation, the size of PPCs in a pH = 6.5 solution increased from 17 nm to 88 nm in 12 h due to self-assembly, while no obvious size change was noticed under the pH = 7.4 condition. The PPCs modified with DBD group (PS-KFx-CAA-DBD) were dissolved in PBS at different pHs for FL measurement; the FL intensity was significantly increased at pH = 6.5 but barely changed at pH = 7.4, which verified acid-induced aggregation. The mechanism of peptide cytotoxicity is rooted in the destructive effect of α-helix structure on mitochondria membranes. Within 12 h, the content of α-helix structure increased slightly from 19.5% to 25.8% at pH = 7.4 but markedly to 58.9% at pH = 6.5. Based on the rapid hydrolysis of PPCs at pH = 6.5, the better recovery of α-helix structure implied a higher therapeutic activity. Therefore, this in vivo self-assembly strategy enables the peptide nanomaterials to penetrate deeper into the tumor cells and thus endows them with enhanced therapeutic efficacy.
