Nanoparticle-based drug delivery system remains a significant challenge in the current treatment of solid tumors,primarily due to their limited penetration capabilities.Herein,we successfully engineer photodynamic gel...Nanoparticle-based drug delivery system remains a significant challenge in the current treatment of solid tumors,primarily due to their limited penetration capabilities.Herein,we successfully engineer photodynamic gel-bombs(DCM@OPR)capable of penetrating deeply into tumor tissues utilizing the photodynamic-triggered explosive energy and receptor-mediated transcytosis,significantly enhancing the therapeutic efficacy of breast cancer.The photodynamic gel-bombs were fabricated by loading powerful components of chlorin e6 and MnO_(2) nanoparticles,as wellas Doxorubicin,into a crosslinked Ca^(2+)-gel.Upon exposure to laser irradiation,the obtained photodynamic gel-bombs are capable of generating explosive energy,resulting in their fragmentation into numerous nanofragments.The photodynamic-triggered explosive energy subsequently drives these nanofragments to deeply penetrate into tumor tissues through gap leakage among tumor cells.In addition,the photodynamictriggered explosive energy also promotes the escape of those therapeutic components(including chlorin e6,MnO_(2) nanoparticles,and doxorubicin)and nanofragments from lysosomes.In the subsequent stages,these nanofragments also exhibit excellent transcytosis capacity,facilitating deep penetration into tumor tissues.As expected,the enhanced penetration and accumulation of therapeutic components into tumor tissues can be achieved,significantly enhancing the anti-proliferation capacity against breast cancer.展开更多
Theα-glucosidase inhibitor acarbose is commercially produced by Actinoplanes sp.and used as a potent drug in the treatment of type-2 diabetes.In order to improve the yield of acarbose,an efficient genetic manipulatio...Theα-glucosidase inhibitor acarbose is commercially produced by Actinoplanes sp.and used as a potent drug in the treatment of type-2 diabetes.In order to improve the yield of acarbose,an efficient genetic manipulation system for Actinoplanes sp.was established.The conjugation system between E.coli carryingØC31-derived integrative plasmids and the mycelia of Actinoplanes sp.SE50/110 was optimized by adjusting the parameters of incubation time of mixed culture(mycelia and E.coli),quantity of recipient cells,donor-to-recipient ratio and the concentration of MgCl2,which resulted in a high conjugation efficiency of 29.4%.Using this integrative system,a cloned acarbose biosynthetic gene cluster was introduced into SE50/110,resulting in a 35%increase of acarbose titer from 2.35 to 3.18 g/L.Alternatively,a pIJ101-derived replicating plasmid combined with the counter-selection system CodA(sm)was constructed for gene inactivation,which has a conjugation frequency as high as 0.52%.Meanwhile,almost all 5-flucytosine-resistant colonies were sensitive to apramycin,among which 75%harbored the successful deletion of targeted genes.Using this replicating vector,the maltooligosyltrehalose synthase gene treY responsible for the accumulation of component C was inactivated,and component C was eliminated as detected by LC-MS.Based on an efficient genetic manipulation system,improved acarbose production and the elimination of component C in our work paved a way for future rational engineering of the acarbose-producing strains.展开更多
基金supported by the National Natural Science Foundation of China(82293650,82293651,82293652,22075127,22275080)GuangDong Basic and Applied Basic Research Foundation(2023A1515111182)President Foundation of Zhujiang Hospital,Southern Medical University(yzij2023qn07).
文摘Nanoparticle-based drug delivery system remains a significant challenge in the current treatment of solid tumors,primarily due to their limited penetration capabilities.Herein,we successfully engineer photodynamic gel-bombs(DCM@OPR)capable of penetrating deeply into tumor tissues utilizing the photodynamic-triggered explosive energy and receptor-mediated transcytosis,significantly enhancing the therapeutic efficacy of breast cancer.The photodynamic gel-bombs were fabricated by loading powerful components of chlorin e6 and MnO_(2) nanoparticles,as wellas Doxorubicin,into a crosslinked Ca^(2+)-gel.Upon exposure to laser irradiation,the obtained photodynamic gel-bombs are capable of generating explosive energy,resulting in their fragmentation into numerous nanofragments.The photodynamic-triggered explosive energy subsequently drives these nanofragments to deeply penetrate into tumor tissues through gap leakage among tumor cells.In addition,the photodynamictriggered explosive energy also promotes the escape of those therapeutic components(including chlorin e6,MnO_(2) nanoparticles,and doxorubicin)and nanofragments from lysosomes.In the subsequent stages,these nanofragments also exhibit excellent transcytosis capacity,facilitating deep penetration into tumor tissues.As expected,the enhanced penetration and accumulation of therapeutic components into tumor tissues can be achieved,significantly enhancing the anti-proliferation capacity against breast cancer.
基金We are grateful to Prof.Yuhui Sun from Wuhan university,China,and the late Prof.Keqian Yang from Institute of Microbiology,Chinese Academy of Sciences,for providing plasmids pWHU2653 and pDR-4-K^*,respectively.This work was supported by grants from the National Natural Science Foundation of China(No.31470157,21661140002)the Ministry of Science and Technology of China(No.2012AA02A706).
文摘Theα-glucosidase inhibitor acarbose is commercially produced by Actinoplanes sp.and used as a potent drug in the treatment of type-2 diabetes.In order to improve the yield of acarbose,an efficient genetic manipulation system for Actinoplanes sp.was established.The conjugation system between E.coli carryingØC31-derived integrative plasmids and the mycelia of Actinoplanes sp.SE50/110 was optimized by adjusting the parameters of incubation time of mixed culture(mycelia and E.coli),quantity of recipient cells,donor-to-recipient ratio and the concentration of MgCl2,which resulted in a high conjugation efficiency of 29.4%.Using this integrative system,a cloned acarbose biosynthetic gene cluster was introduced into SE50/110,resulting in a 35%increase of acarbose titer from 2.35 to 3.18 g/L.Alternatively,a pIJ101-derived replicating plasmid combined with the counter-selection system CodA(sm)was constructed for gene inactivation,which has a conjugation frequency as high as 0.52%.Meanwhile,almost all 5-flucytosine-resistant colonies were sensitive to apramycin,among which 75%harbored the successful deletion of targeted genes.Using this replicating vector,the maltooligosyltrehalose synthase gene treY responsible for the accumulation of component C was inactivated,and component C was eliminated as detected by LC-MS.Based on an efficient genetic manipulation system,improved acarbose production and the elimination of component C in our work paved a way for future rational engineering of the acarbose-producing strains.
