Disulfide bond-bridging strategy has been extensively utilized to construct tumor specificity-responsive aliphatic prodrug nanoparticles(PNPs) for precise cancer therapy. Yet, there is no research shedding light on th...Disulfide bond-bridging strategy has been extensively utilized to construct tumor specificity-responsive aliphatic prodrug nanoparticles(PNPs) for precise cancer therapy. Yet, there is no research shedding light on the impacts of the saturation and cis-trans configuration of aliphatic tails on the self-assembly capacity of disulfide bond-linked prodrugs and the in vivo delivery fate of PNPs. Herein, five disulfide bond-linked docetaxelfatty acid prodrugs are designed and synthesized by using stearic acid, elaidic acid, oleic acid, linoleic acid and linolenic acid as the aliphatic tails, respectively. Interestingly, the cistrans configuration of aliphatic tails significantly influences the self-assembly features of prodrugs, and elaidic acid-linked prodrug with a trans double bond show poor self-assembly capacity. Although the aliphatic tails have almost no effect on the redox-sensitive drug release and cytotoxicity, different aliphatic tails significantly influence the chemical stability of prodrugs and the colloidal stability of PNPs, thus affecting the in vivo pharmacokinetics, biodistribution and antitumor efficacy of PNPs. Our findings illustrate how aliphatic tails affect the assembly characteristic of disulfide bond-linked aliphatic prodrugs and the in vivo delivery fate of PNPs, and thus provide theoretical basis for future development of disulfide bond-bridged aliphatic prodrugs.展开更多
A new approach is described for delivering small interfering RNA(siRNA)into cancer cells by noncovalently complexing unmodifi ed siRNA with pristine single-walled carbon nanotubes(SWCNTs).The complexes were prepared b...A new approach is described for delivering small interfering RNA(siRNA)into cancer cells by noncovalently complexing unmodifi ed siRNA with pristine single-walled carbon nanotubes(SWCNTs).The complexes were prepared by simple sonication of pristine SWCNTs in a solution of siRNA,which then served both as the cargo and as the suspending agent for the SWCNTs.When complexes containing siRNA targeted to hypoxia-inducible factor 1 alpha(HIF-1)were added to cells growing in serum containing culture media,there was strong specific inhibition of cellular HIF-1 activity.The ability to obtain a biological response to SWCNT/siRNA complexes was seen in a wide variety of cancer cell types.Moreover,intratumoral administration of SWCNT-HIF-1 siRNA complexes in mice bearing MiaPaCa-2/HRE tumors signifi cantly inhibited the activity of tumor HIF-1.As elevated levels of HIF-1 are found in many human cancers and are associated with resistance to therapy and decreased patient survival,these results imply that SWCNT/siRNA complexes may have value as therapeutic agents.展开更多
基金funding from the National Natural Science Foundation of China(No.81703451 and 81773656)the Excellent Youth Science Foundation of Liaoning Province(No.2020-YQ-06)+2 种基金the Liaoning Revitalization Talents Program(No.XLYC1808017 and XLYC1907129)the China Postdoctoral Science Foundation(No.2020M670794)the Science and Technology Major Project of Liaoning(No.2019JH1/10300004)。
文摘Disulfide bond-bridging strategy has been extensively utilized to construct tumor specificity-responsive aliphatic prodrug nanoparticles(PNPs) for precise cancer therapy. Yet, there is no research shedding light on the impacts of the saturation and cis-trans configuration of aliphatic tails on the self-assembly capacity of disulfide bond-linked prodrugs and the in vivo delivery fate of PNPs. Herein, five disulfide bond-linked docetaxelfatty acid prodrugs are designed and synthesized by using stearic acid, elaidic acid, oleic acid, linoleic acid and linolenic acid as the aliphatic tails, respectively. Interestingly, the cistrans configuration of aliphatic tails significantly influences the self-assembly features of prodrugs, and elaidic acid-linked prodrug with a trans double bond show poor self-assembly capacity. Although the aliphatic tails have almost no effect on the redox-sensitive drug release and cytotoxicity, different aliphatic tails significantly influence the chemical stability of prodrugs and the colloidal stability of PNPs, thus affecting the in vivo pharmacokinetics, biodistribution and antitumor efficacy of PNPs. Our findings illustrate how aliphatic tails affect the assembly characteristic of disulfide bond-linked aliphatic prodrugs and the in vivo delivery fate of PNPs, and thus provide theoretical basis for future development of disulfide bond-bridged aliphatic prodrugs.
基金the M.D.Anderson Cancer Center from the NIH(CA-77204 and CA-109552)to Rice University from the Welch Foundation(C-0807)+1 种基金the NSF Center for Biological and Environmental Nanotechnology(EEC-0647452)the Alliance for NanoHealth(NASA JSC-NNJ06HC25G).
文摘A new approach is described for delivering small interfering RNA(siRNA)into cancer cells by noncovalently complexing unmodifi ed siRNA with pristine single-walled carbon nanotubes(SWCNTs).The complexes were prepared by simple sonication of pristine SWCNTs in a solution of siRNA,which then served both as the cargo and as the suspending agent for the SWCNTs.When complexes containing siRNA targeted to hypoxia-inducible factor 1 alpha(HIF-1)were added to cells growing in serum containing culture media,there was strong specific inhibition of cellular HIF-1 activity.The ability to obtain a biological response to SWCNT/siRNA complexes was seen in a wide variety of cancer cell types.Moreover,intratumoral administration of SWCNT-HIF-1 siRNA complexes in mice bearing MiaPaCa-2/HRE tumors signifi cantly inhibited the activity of tumor HIF-1.As elevated levels of HIF-1 are found in many human cancers and are associated with resistance to therapy and decreased patient survival,these results imply that SWCNT/siRNA complexes may have value as therapeutic agents.