Multidrug resistance(MDR) has been considered as a huge challenge to the effective chemotherapy. Therefore, it is necessary to develop new strategies to effectively overcome MDR. Here,based on the previous research of...Multidrug resistance(MDR) has been considered as a huge challenge to the effective chemotherapy. Therefore, it is necessary to develop new strategies to effectively overcome MDR. Here,based on the previous research of N-(2-hydroxypropyl)methacrylamide(HPMA) polymer–drug conjugates, we designed an effective system that combined drug-efflux circumvention and mitochondria targeting of anticancer drug doxorubicin(Dox). Briefly, Dox was modified with mitochondrial membrane penetrating peptide(MPP) and then attached to(HPMA) copolymers(P-M-Dox). Our study showed that macromolecular HPMA copolymers successfully bypassed drug efflux pumps and escorted Dox into resistant MCF-7/ADR cells via endocytic pathway. Subsequently, the mitochondria accumulation of drugs was significantly enhanced with 11.6-fold increase by MPP modification. The excellent mitochondria targeting then resulted in significant enhancement of reactive oxygen species(ROS) as well as reduction of adenosine triphosphate(ATP)production, which could further inhibit drug efflux and resistant cancer cell growth. By reversing Dox resistance, P-M-Dox achieved much better suppression in the growth of 3D MCF-7/ADR tumor spheroids compared with free Dox. Hence, our study provides a promising approach to treat drug-resistant cancer through simultaneous drug efflux circumvention and direct mitochondria delivery.展开更多
N-（2-Hydroxypropyl） methacrylamide copolymer-5-fluorouracil （PHPMA-FU） conjugates were synthesized by a novel and simplified synthetic route, and characterized by UV, FTIR and HPLC analyses. The conjugated content...N-（2-Hydroxypropyl） methacrylamide copolymer-5-fluorouracil （PHPMA-FU） conjugates were synthesized by a novel and simplified synthetic route, and characterized by UV, FTIR and HPLC analyses. The conjugated content of 5-fluorouracil （5-FU） was 3.41 ± 0.07 wt%. The stabilities of PHPMA-FU conjugates under different conditions were studied. The results showed that HPMA copolymer was a potential carrier for tumor-targeting delivery of 5-FU.展开更多
To develop new radiopharmaceuticals for the interventional radionuclide therapy of recurrent hepatocellular carcinoma, poly（HPMA）-APMA-DTPA[HPMA=N-（2-hydroxypropyl） methacrylamide; APMA=N-（3-aminopropyl）methacry...To develop new radiopharmaceuticals for the interventional radionuclide therapy of recurrent hepatocellular carcinoma, poly（HPMA）-APMA-DTPA[HPMA=N-（2-hydroxypropyl） methacrylamide; APMA=N-（3-aminopropyl）methacrylamide; DTPA=diethylenetriaminepentaacetic acidl was synthesized by free radical precipitation polymerization in acetone/dimethylsulfoxide with N,N＇-azobis（isobutyronitrile） as the initiator. The copolymers were characterized with nuclear magnetic resonance（NMR） spectroscopy and gel permeation chromatography（GPC, Mn=2.2xl04, Mw/Mn=l.38）. Subsequently, poly（HPMA）-APMA-DTPA was conjugated with 99mTC radionuclide. Prolonged retention of poly（HPMA）-APMA-DTPA conjugate within the tumor tissues was demonstrated by single-photon emission computed tomography computed tomography（SPECT-CT） at 1, 2, 4 and 24 h following intra-tumoral injection of the conjugate to hepatocellular carcinoma xenografts in mice. DTPA-99mTc was also synthesized and characterized for comparison. The data suggest that the poly（HPMA）-APMA-DTPA conjugates might be useful for the interventional radionuclide therapy of recurrent hepatocellular carcinoma in humans.展开更多
To develop new tumor targeting macromolecular conjugates,poly（HPMA）-SD-APMA-DTPA（HPMA：N-（2-hydroxypropyl）- methacrylamide;APMA：N-（3-ammopropyl）methacrylamide;DTPA：diethylenetriaminepentaacetic acid;SD：sulfa...To develop new tumor targeting macromolecular conjugates,poly（HPMA）-SD-APMA-DTPA（HPMA：N-（2-hydroxypropyl）- methacrylamide;APMA：N-（3-ammopropyl）methacrylamide;DTPA：diethylenetriaminepentaacetic acid;SD：sulfadiazine） was synthesized and characterized.The poly（HPMA）-SD-DTPA conjugates were radiolabeled with the radionuclide ^（99m）Tc and tested for uptake by cultured H22 cells in vitro.DTPA-^（99m）Tc（radiotracer 1） and poly（HPMA）-DTPA-^（99m）Tc（radiotracer 2） were also synthesized and characterized for comparison.The uptake of poly（HPMA）-SD-DTPA-^（99m）Tc（radiotracer 3,34.76%） was significantly higher than that of poly（HPMA）-DTPA-^（99m）Tc（16.40%）,indicating that uptake of the poly（HPMA）-SD-DTPA-^（99m）T was active binding.The uptake of poly（HPMA）-DTPA-^（99m）Tc was significantly higher than that of DTPA-^（99m）Tc（2.98%）, suggesting that uptake of the poly（HPMA）-DTPA-^（99m）T was passive binding.The data suggest that the poly（HPMA）-SDAPMA -DTPA conjugates might be useful as tumor targeting macromolecular conjugates.展开更多
基金financial support from the National Natural Science Foundation for Distinguished Young Scholars (81625023, China)the National Natural Science Foundation of China (81473167)Sichuan Youth Science and Technology Innovation Research Team Funding (2016TD0001, China)
文摘Multidrug resistance(MDR) has been considered as a huge challenge to the effective chemotherapy. Therefore, it is necessary to develop new strategies to effectively overcome MDR. Here,based on the previous research of N-(2-hydroxypropyl)methacrylamide(HPMA) polymer–drug conjugates, we designed an effective system that combined drug-efflux circumvention and mitochondria targeting of anticancer drug doxorubicin(Dox). Briefly, Dox was modified with mitochondrial membrane penetrating peptide(MPP) and then attached to(HPMA) copolymers(P-M-Dox). Our study showed that macromolecular HPMA copolymers successfully bypassed drug efflux pumps and escorted Dox into resistant MCF-7/ADR cells via endocytic pathway. Subsequently, the mitochondria accumulation of drugs was significantly enhanced with 11.6-fold increase by MPP modification. The excellent mitochondria targeting then resulted in significant enhancement of reactive oxygen species(ROS) as well as reduction of adenosine triphosphate(ATP)production, which could further inhibit drug efflux and resistant cancer cell growth. By reversing Dox resistance, P-M-Dox achieved much better suppression in the growth of 3D MCF-7/ADR tumor spheroids compared with free Dox. Hence, our study provides a promising approach to treat drug-resistant cancer through simultaneous drug efflux circumvention and direct mitochondria delivery.
基金supported by the National Natural Science Foundation of China(No.30500636)Ministry of Education(NCET-06-0786).
文摘N-（2-Hydroxypropyl） methacrylamide copolymer-5-fluorouracil （PHPMA-FU） conjugates were synthesized by a novel and simplified synthetic route, and characterized by UV, FTIR and HPLC analyses. The conjugated content of 5-fluorouracil （5-FU） was 3.41 ± 0.07 wt%. The stabilities of PHPMA-FU conjugates under different conditions were studied. The results showed that HPMA copolymer was a potential carrier for tumor-targeting delivery of 5-FU.
基金the National Natural Science Foundation of China
文摘To develop new radiopharmaceuticals for the interventional radionuclide therapy of recurrent hepatocellular carcinoma, poly（HPMA）-APMA-DTPA[HPMA=N-（2-hydroxypropyl） methacrylamide; APMA=N-（3-aminopropyl）methacrylamide; DTPA=diethylenetriaminepentaacetic acidl was synthesized by free radical precipitation polymerization in acetone/dimethylsulfoxide with N,N＇-azobis（isobutyronitrile） as the initiator. The copolymers were characterized with nuclear magnetic resonance（NMR） spectroscopy and gel permeation chromatography（GPC, Mn=2.2xl04, Mw/Mn=l.38）. Subsequently, poly（HPMA）-APMA-DTPA was conjugated with 99mTC radionuclide. Prolonged retention of poly（HPMA）-APMA-DTPA conjugate within the tumor tissues was demonstrated by single-photon emission computed tomography computed tomography（SPECT-CT） at 1, 2, 4 and 24 h following intra-tumoral injection of the conjugate to hepatocellular carcinoma xenografts in mice. DTPA-99mTc was also synthesized and characterized for comparison. The data suggest that the poly（HPMA）-APMA-DTPA conjugates might be useful for the interventional radionuclide therapy of recurrent hepatocellular carcinoma in humans.
基金the National Natural Science Foundation of China(No.20964003)for funding
文摘To develop new tumor targeting macromolecular conjugates,poly（HPMA）-SD-APMA-DTPA（HPMA：N-（2-hydroxypropyl）- methacrylamide;APMA：N-（3-ammopropyl）methacrylamide;DTPA：diethylenetriaminepentaacetic acid;SD：sulfadiazine） was synthesized and characterized.The poly（HPMA）-SD-DTPA conjugates were radiolabeled with the radionuclide ^（99m）Tc and tested for uptake by cultured H22 cells in vitro.DTPA-^（99m）Tc（radiotracer 1） and poly（HPMA）-DTPA-^（99m）Tc（radiotracer 2） were also synthesized and characterized for comparison.The uptake of poly（HPMA）-SD-DTPA-^（99m）Tc（radiotracer 3,34.76%） was significantly higher than that of poly（HPMA）-DTPA-^（99m）Tc（16.40%）,indicating that uptake of the poly（HPMA）-SD-DTPA-^（99m）T was active binding.The uptake of poly（HPMA）-DTPA-^（99m）Tc was significantly higher than that of DTPA-^（99m）Tc（2.98%）, suggesting that uptake of the poly（HPMA）-DTPA-^（99m）T was passive binding.The data suggest that the poly（HPMA）-SDAPMA -DTPA conjugates might be useful as tumor targeting macromolecular conjugates.
