Stimuli-responsive drug delivery systems based on polymeric micelles can achieve controlled drug release to improve the therapeutic outcome and reduce unwanted systematic toxicity and side effects of the cytotoxic dru...Stimuli-responsive drug delivery systems based on polymeric micelles can achieve controlled drug release to improve the therapeutic outcome and reduce unwanted systematic toxicity and side effects of the cytotoxic drug in chemotherapy but often face challenging synthesis and purification of functionalized biocompatible polymer materials and low drug loading efficiency. In the present study, we reported a novel redox-responsive self-assembly polymeric micelle system, mPEG-β-CD/Ad-SS-CPT, to achieve high loading efficiency and selective delivery of camptothecin(CPT) in a reductive environment inside cancer cells. The host-vip supramolecular micelles utilized a simple β-CD modified PEG, mPEG-β-cyclodextrin(mPEG-β-CD), as the polymeric host with the ease of synthesis and purification. The vip prodrug Ad-SS-CPT contained the disulfide bond as the redox sensitivity group. The selective cleavage of disulfide bond and subsequent drug release in a reductive environment could potentially reduce system toxicity and improve the therapeutic outcome of CPT. In vitro studies showed that the micelles exhibited excellent cytotoxicity against He La cells comparable to the free drug. The host-vip polymeric micelles also showed great potentials for multi-drug co-delivery. Collectively, our current findings provided a general and convenient approach to design drug delivery systems based on stimuli-responsive polymeric micelles for disease treatment.展开更多
β-cyclodextrin (CD) grafted N-maleoyl chitosan (CD-g-NMCS) with two different degrees of substitution (DS) of N-maleoyl (DS = 21.2% and 30.5%) were synthesized from maleic anhydride and chitosan bearing pendant cyclo...β-cyclodextrin (CD) grafted N-maleoyl chitosan (CD-g-NMCS) with two different degrees of substitution (DS) of N-maleoyl (DS = 21.2% and 30.5%) were synthesized from maleic anhydride and chitosan bearing pendant cyclodextrin (CD-g-CS). CD-g-NMCS based nanoparticles were prepared via an ionic gelation method together with chitosan and CD-g-CS nanoparticles.The size and zeta potential of prepared CD-g-NMCS nanoparticles were 179.2~274.0 nm and 36.2~42.4 m V, respectively. In vitro stability test indicated that CD-g-NMCS nanoparticles were more stable in phosphate-buffered saline compared with chitosan nanoparticles. Moreover, a poorly water-soluble drug, ketoprofen (KTP), was selected as a model drug to study the obtained nanoparticle’s potentials as drug delivery carriers. The drug loading efficiency of CD-g-NMCS20 nanoparticles were 14.8% for KTP. MTT assay showed that KTP loaded CD-g-NMCS nanoparticles were safe drug carriers. Notably, in vitro drug release studies showed that KTP was released in a sustained-release manner for the nanoparticles. The pharmacokinetic of drug loaded CD-g-NMCS20 nanoparticles were evaluated in rats after intravenous administration. The results of studies revealed that, compared with free KTP, KTP loaded CD-g-NMCS20 nanoparticles exhibited a significant increase in AUC0→24h and mean residence time by 6.6-fold and 2.9-fold, respectively. Therefore, CD-g-NMCS nanoparticles could be used as a novel promising nanoparticle-based drug delivery system for sustained release of poorly water-soluble drugs. The carboxylic acid groups of the CD-g-NMCS molecule provide convenient sites for further structural modifications including introduction of tissue-or disease-specific targeting groups.展开更多
This paper presented an interesting nanoparticle-based drug delivery system with morphology transition behavior depending on the content of exposed PEG chain on the particle surface, which is adjustable by addition of...This paper presented an interesting nanoparticle-based drug delivery system with morphology transition behavior depending on the content of exposed PEG chain on the particle surface, which is adjustable by addition of different amount of cyclodextrin(α-CD). The effect of α-CD inclusion to the self-assembly behavior of methoxy polyethylene glycol(mPEG) grafted chitosan(CS) was studied. The results showed that the mPEG grafted chitosan(mPEG-g-CS) forms self-assembled nanoparticles with either micelle or hollow sphere morphology depending on the ratio of α-CD to mPEG, as characterized by atomic force microscopy(AFM), transmission electron microscopy(TEM), and X-ray diffraction(XRD). Their sizes and zeta potential increased from 257.6 nmto 768.2 nm and from +4.5 mV to +11.6 mV, respectively, with the increasing amount of α-CD. The correlation between zeta potential and particle size of α-CD/mPEG-g-CS nanoparticles indicated varied PEG density on surface of nanoparticles. Based on the above experimental observations, a likely mechanism for the morphological transition of the rod-coil graft copolymer mPEG-g-CS was proposed.展开更多
A novel oral protein delivery system with enhanced intestinal penetration and improved antigen stability based on chitosan(CS) nanoparticles and antigen-cyclodextrin(CD) inclusion complex was prepared by a precipitati...A novel oral protein delivery system with enhanced intestinal penetration and improved antigen stability based on chitosan(CS) nanoparticles and antigen-cyclodextrin(CD) inclusion complex was prepared by a precipitation/coacervation method. Ovalbumin(OVA) as a model antigen was firstly encapsulated by cyclodextrin, either β-cyclodextrin( β-CD) or carboxymethyl-hydroxypropyl-β-cyclodextrin(CM-HP-β-CD) and formed OVA-CD inclusion complexes, which were then loaded to chitosan nanoparticles to form OVA loaded β-CD/CS or CM-HP-β-CD/CS nanoparticles with uniform particle size(836.3 and 779.2 nm, respectively) and improved OVA loading efficiency(27.6% and 20.4%, respectively). In vitro drug release studies mimicking oral delivery condition of OVA loaded CD/CS nanoparticles showed low initial releases at p H 1.2 for 2 h less than 3.0% and a delayed release which was below to 30% at p H 6.8 for further 72 h. More importantly, after oral administration of OVA loaded β-CD/CS nanoparticles to Balb/c mice, OVA-specific sIgA levels in jejunum of OVA loaded β-CD/CS nanoparticles were 3.6-fold and 1.9-fold higher than that of OVA solution and OVA loaded chitosan nanoparticles, respectively. In vivo evaluation results showed that OVA loaded CD/CS nanoparticles could enhance its efficacy for inducing intestinal mucosal immune response. In conclusion, our data suggested that CD/CS nanoparticles could serve as a promising antigen-delivery system for oral vaccination.展开更多
A light-switchable transgene system called LightOn gene expression system could regulate gene expression with a high on/off ratio under blue light,and have great potential for spatiotemporally controllable gene expres...A light-switchable transgene system called LightOn gene expression system could regulate gene expression with a high on/off ratio under blue light,and have great potential for spatiotemporally controllable gene expression.We developed a nanoparticle drug delivery system(NDDS)to achieve tumor microenvironment-responsive and targeted delivery of diphtheria toxin A(DTA)fragment-encoded plasmids to tumor sites.The expression of DTA was induced by exposure to blue light.Nanoparticles composed of polyethylenimine and vitamin E succinate linked by a disulfide bond,and PEGylated hyaluronic acid modified with RGD peptide,accumulated in tumor tissues and were actively internalized into 4 T1 cells via dual targeting to CD44 andαvβ3 receptors.The LightOn gene expression system was able to control target protein expression through regulation of the intensity or duration of blue light exposure.In vitro studies showed that lisht-induced DTA expression reduced 4 T1 cell viability and induced apoptosis.Furthermore,the LightOn gene expression system enabled spatiotemporal control of the expression of DTA in a mouse 4 T1 tumor xenogratt model,which resulted in excellent antitumor effects,reduced tumor angiogenesis,and no systemic toxicity.The combination of the LightOn gene expression system and NDDS may be an effective strategy for treatment of breast cancer.展开更多
基金National Key Research and Development Program of China (Grant No. 2019YFA0904800)Science and Technology Commission of Shanghai Municipality (Grant No. 11DZ2260600 and 10DZ2220500)Shanghai Natural Science Fund (Grant No. 20ZR1414700)。
文摘Stimuli-responsive drug delivery systems based on polymeric micelles can achieve controlled drug release to improve the therapeutic outcome and reduce unwanted systematic toxicity and side effects of the cytotoxic drug in chemotherapy but often face challenging synthesis and purification of functionalized biocompatible polymer materials and low drug loading efficiency. In the present study, we reported a novel redox-responsive self-assembly polymeric micelle system, mPEG-β-CD/Ad-SS-CPT, to achieve high loading efficiency and selective delivery of camptothecin(CPT) in a reductive environment inside cancer cells. The host-vip supramolecular micelles utilized a simple β-CD modified PEG, mPEG-β-cyclodextrin(mPEG-β-CD), as the polymeric host with the ease of synthesis and purification. The vip prodrug Ad-SS-CPT contained the disulfide bond as the redox sensitivity group. The selective cleavage of disulfide bond and subsequent drug release in a reductive environment could potentially reduce system toxicity and improve the therapeutic outcome of CPT. In vitro studies showed that the micelles exhibited excellent cytotoxicity against He La cells comparable to the free drug. The host-vip polymeric micelles also showed great potentials for multi-drug co-delivery. Collectively, our current findings provided a general and convenient approach to design drug delivery systems based on stimuli-responsive polymeric micelles for disease treatment.
基金supported by the National Science Foundation of China (No.21577037)Shanghai Committee of Science and Technology (No.17ZR1406600),Shanghai Committee of Science and Technology (grant No.11DZ2260600)Science and Technology Commission of Shanghai Municipality (STCSM,contract No.10DZ2220500)
文摘β-cyclodextrin (CD) grafted N-maleoyl chitosan (CD-g-NMCS) with two different degrees of substitution (DS) of N-maleoyl (DS = 21.2% and 30.5%) were synthesized from maleic anhydride and chitosan bearing pendant cyclodextrin (CD-g-CS). CD-g-NMCS based nanoparticles were prepared via an ionic gelation method together with chitosan and CD-g-CS nanoparticles.The size and zeta potential of prepared CD-g-NMCS nanoparticles were 179.2~274.0 nm and 36.2~42.4 m V, respectively. In vitro stability test indicated that CD-g-NMCS nanoparticles were more stable in phosphate-buffered saline compared with chitosan nanoparticles. Moreover, a poorly water-soluble drug, ketoprofen (KTP), was selected as a model drug to study the obtained nanoparticle’s potentials as drug delivery carriers. The drug loading efficiency of CD-g-NMCS20 nanoparticles were 14.8% for KTP. MTT assay showed that KTP loaded CD-g-NMCS nanoparticles were safe drug carriers. Notably, in vitro drug release studies showed that KTP was released in a sustained-release manner for the nanoparticles. The pharmacokinetic of drug loaded CD-g-NMCS20 nanoparticles were evaluated in rats after intravenous administration. The results of studies revealed that, compared with free KTP, KTP loaded CD-g-NMCS20 nanoparticles exhibited a significant increase in AUC0→24h and mean residence time by 6.6-fold and 2.9-fold, respectively. Therefore, CD-g-NMCS nanoparticles could be used as a novel promising nanoparticle-based drug delivery system for sustained release of poorly water-soluble drugs. The carboxylic acid groups of the CD-g-NMCS molecule provide convenient sites for further structural modifications including introduction of tissue-or disease-specific targeting groups.
基金supported by Science and Technology Commission of Shanghai Municipality (Nos. 17ZR1406600, 10DZ2220500, 11DZ2260600)National Natural Science Foundation of China (No.21577037)
文摘This paper presented an interesting nanoparticle-based drug delivery system with morphology transition behavior depending on the content of exposed PEG chain on the particle surface, which is adjustable by addition of different amount of cyclodextrin(α-CD). The effect of α-CD inclusion to the self-assembly behavior of methoxy polyethylene glycol(mPEG) grafted chitosan(CS) was studied. The results showed that the mPEG grafted chitosan(mPEG-g-CS) forms self-assembled nanoparticles with either micelle or hollow sphere morphology depending on the ratio of α-CD to mPEG, as characterized by atomic force microscopy(AFM), transmission electron microscopy(TEM), and X-ray diffraction(XRD). Their sizes and zeta potential increased from 257.6 nmto 768.2 nm and from +4.5 mV to +11.6 mV, respectively, with the increasing amount of α-CD. The correlation between zeta potential and particle size of α-CD/mPEG-g-CS nanoparticles indicated varied PEG density on surface of nanoparticles. Based on the above experimental observations, a likely mechanism for the morphological transition of the rod-coil graft copolymer mPEG-g-CS was proposed.
基金supported by Science and Technology Commission of Shanghai Municipality(No.17ZR1406600)National Science Foundation of China(No.21577037)sponsored by Science and Technology Commission of Shanghai Municipality(No.10DZ2220500 and No.11DZ2260600)
文摘A novel oral protein delivery system with enhanced intestinal penetration and improved antigen stability based on chitosan(CS) nanoparticles and antigen-cyclodextrin(CD) inclusion complex was prepared by a precipitation/coacervation method. Ovalbumin(OVA) as a model antigen was firstly encapsulated by cyclodextrin, either β-cyclodextrin( β-CD) or carboxymethyl-hydroxypropyl-β-cyclodextrin(CM-HP-β-CD) and formed OVA-CD inclusion complexes, which were then loaded to chitosan nanoparticles to form OVA loaded β-CD/CS or CM-HP-β-CD/CS nanoparticles with uniform particle size(836.3 and 779.2 nm, respectively) and improved OVA loading efficiency(27.6% and 20.4%, respectively). In vitro drug release studies mimicking oral delivery condition of OVA loaded CD/CS nanoparticles showed low initial releases at p H 1.2 for 2 h less than 3.0% and a delayed release which was below to 30% at p H 6.8 for further 72 h. More importantly, after oral administration of OVA loaded β-CD/CS nanoparticles to Balb/c mice, OVA-specific sIgA levels in jejunum of OVA loaded β-CD/CS nanoparticles were 3.6-fold and 1.9-fold higher than that of OVA solution and OVA loaded chitosan nanoparticles, respectively. In vivo evaluation results showed that OVA loaded CD/CS nanoparticles could enhance its efficacy for inducing intestinal mucosal immune response. In conclusion, our data suggested that CD/CS nanoparticles could serve as a promising antigen-delivery system for oral vaccination.
基金supportedby Shanghai Municipal Natural Science Foundation(No.17ZR1406600,China)Science and Technology Commission of Shanghai Municipality(No.10DZ2220500,China)+1 种基金The Shanghai Committee of Science and Technology(Grant No.11DZ2260600,China)National Natural Science Foundation of China(Grant No.81973700)
文摘A light-switchable transgene system called LightOn gene expression system could regulate gene expression with a high on/off ratio under blue light,and have great potential for spatiotemporally controllable gene expression.We developed a nanoparticle drug delivery system(NDDS)to achieve tumor microenvironment-responsive and targeted delivery of diphtheria toxin A(DTA)fragment-encoded plasmids to tumor sites.The expression of DTA was induced by exposure to blue light.Nanoparticles composed of polyethylenimine and vitamin E succinate linked by a disulfide bond,and PEGylated hyaluronic acid modified with RGD peptide,accumulated in tumor tissues and were actively internalized into 4 T1 cells via dual targeting to CD44 andαvβ3 receptors.The LightOn gene expression system was able to control target protein expression through regulation of the intensity or duration of blue light exposure.In vitro studies showed that lisht-induced DTA expression reduced 4 T1 cell viability and induced apoptosis.Furthermore,the LightOn gene expression system enabled spatiotemporal control of the expression of DTA in a mouse 4 T1 tumor xenogratt model,which resulted in excellent antitumor effects,reduced tumor angiogenesis,and no systemic toxicity.The combination of the LightOn gene expression system and NDDS may be an effective strategy for treatment of breast cancer.
