Small-molecule prodrug nanoassemblies have emerged as efficient antitumor drug delivery systems.However,in the case of camptothecins-based prodrug nanoassemblies,linear aliphatic side chain modification often results ...Small-molecule prodrug nanoassemblies have emerged as efficient antitumor drug delivery systems.However,in the case of camptothecins-based prodrug nanoassemblies,linear aliphatic side chain modification often results in rod-shaped or irregularly shaped nanoassemblies,which are highly unfavorable for sterilization through filtration,and may cause capillary blockage upon intravenous injection.The rational design of camptothecins-based prodrug nanoassemblies remains a challenge.Herein,we propose that branched aliphatic alcohol(BAA)functionalization could fine-tune the structure-tolerance-antitumor efficacy axis of prodrug nanoassemblies.Correspondingly,four SN38-BAA prodrugs were synthesized by conjugating 7-ethyl-10-hydroxycamptothecin(SN38)with BAAs of varying lengths via a tumor redox-responsive disulfide bond,which self-assemble into uniform spherical nanoparticles.The length of BAA was found to significant impact the multiple drug delivery process,including colloidal stability,drug release profiles and pharmacokinetics.Overall,SN38-C21 NPs(SN38-11-heneicosanol nanoparticles),featuring the longest BAA,showcased multiple therapeutic advantages,ultimately culminating the optimal antitumor efficacy and tolerance.The findings underscore the potential of BAA functionalization in strengthening the therapeutic outcomes of prodrug nanoassemblies,and provide valuable insights for developing translational camptothecins-based nanomedicines.展开更多
Nanoparticulate drug delivery systems(Nano-DDSs) have emerged as possible solution to the obstacles of anticancer drug delivery. However, the clinical outcomes and translation are restricted by several drawbacks, such...Nanoparticulate drug delivery systems(Nano-DDSs) have emerged as possible solution to the obstacles of anticancer drug delivery. However, the clinical outcomes and translation are restricted by several drawbacks, such as low drug loading, premature drug leakage and carrier-related toxicity.Recently, pure drug nano-assemblies(PDNAs), fabricated by the self-assembly or co-assembly of pure drug molecules, have attracted considerable attention. Their facile and reproducible preparation technique helps to remove the bottleneck of nanomedicines including quality control, scale-up production and clinical translation. Acting as both carriers and cargos, the carrier-free PDNAs have an ultra-high or even100% drug loading. In addition, combination therapies based on PDNAs could possibly address the most intractable problems in cancer treatment, such as tumor metastasis and drug resistance. In the present review, the latest development of PDNAs for cancer treatment is overviewed. First, PDNAs are classified according to the composition of drug molecules, and the assembly mechanisms are discussed. Furthermore, the co-delivery of PDNAs for combination therapies is summarized, with special focus on the improvement of therapeutic outcomes. Finally, future prospects and challenges of PDNAs for efficient cancer therapy are spotlighted.展开更多
The unique characteristics of the tumor microenvironment(TME)could be exploited to develop antitumor nanomedicine strategies.However,in many cases,the actual therapeutic effect is far from reaching our expectations du...The unique characteristics of the tumor microenvironment(TME)could be exploited to develop antitumor nanomedicine strategies.However,in many cases,the actual therapeutic effect is far from reaching our expectations due to the notable tumor heterogeneity.Given the amplified characteristics of TME regulated by vascular disrupting agents(VDAs),nanomedicines may achieve unexpected improved efficacy.Herein,we fabricate platelet membrane-fusogenic liposomes(PML/DP&PPa),namely“platesomes”,which actively load the hypoxia-activated pro-prodrug DMG-PR104A(DP)and physically encapsulate the photosensitizer pyropheophorbide a(PPa).Considering the different stages of tumor vascular collapse and shutdown induced by a VDA combretastatin-A4 phosphate(CA4P),PML/DP&PPa is injected 3 h after intraperitoneal administration of CA4P.First,CA4P-mediated tumor hemorrhage amplifies the enhanced permeation and retention(EPR)effect,and the platesome-biological targeting further promotes the tumor accumulation of PML/DP&PPa.Besides,CA4P-induced vascular occlusion inhibits oxygen supply,followed by photodynamic therapy-caused acute tumor hypoxia.This prolonged extreme hypoxia contributes to the complete activation of DP and then high inhibitory effect on tumor growth and metastasis.Thus,such a combining strategy of artificially-regulated TME and bio-inspired platesomes pronouncedly improves tumor drug delivery and boosts tumor hypoxia-selective activation,and provides a preferable solution to high-efficiency cancer therapy.展开更多
基金supported by National Natural Science Foundation of China(Nos.82272151,82204318 and 82173766)Doctoral Scientific Research Staring Foundation of Liaoning Province(No.2021-BS-130)+1 种基金General Program of Department of Education of Liaoning Province(No.LJKZ0953)Shenyang Young and Middle-aged Science and Technology Innovation Talent Support Program(No.RC220389).
文摘Small-molecule prodrug nanoassemblies have emerged as efficient antitumor drug delivery systems.However,in the case of camptothecins-based prodrug nanoassemblies,linear aliphatic side chain modification often results in rod-shaped or irregularly shaped nanoassemblies,which are highly unfavorable for sterilization through filtration,and may cause capillary blockage upon intravenous injection.The rational design of camptothecins-based prodrug nanoassemblies remains a challenge.Herein,we propose that branched aliphatic alcohol(BAA)functionalization could fine-tune the structure-tolerance-antitumor efficacy axis of prodrug nanoassemblies.Correspondingly,four SN38-BAA prodrugs were synthesized by conjugating 7-ethyl-10-hydroxycamptothecin(SN38)with BAAs of varying lengths via a tumor redox-responsive disulfide bond,which self-assemble into uniform spherical nanoparticles.The length of BAA was found to significant impact the multiple drug delivery process,including colloidal stability,drug release profiles and pharmacokinetics.Overall,SN38-C21 NPs(SN38-11-heneicosanol nanoparticles),featuring the longest BAA,showcased multiple therapeutic advantages,ultimately culminating the optimal antitumor efficacy and tolerance.The findings underscore the potential of BAA functionalization in strengthening the therapeutic outcomes of prodrug nanoassemblies,and provide valuable insights for developing translational camptothecins-based nanomedicines.
基金supported by Liaoning Science&Technology project(2019-ZD-0465,China)。
文摘Nanoparticulate drug delivery systems(Nano-DDSs) have emerged as possible solution to the obstacles of anticancer drug delivery. However, the clinical outcomes and translation are restricted by several drawbacks, such as low drug loading, premature drug leakage and carrier-related toxicity.Recently, pure drug nano-assemblies(PDNAs), fabricated by the self-assembly or co-assembly of pure drug molecules, have attracted considerable attention. Their facile and reproducible preparation technique helps to remove the bottleneck of nanomedicines including quality control, scale-up production and clinical translation. Acting as both carriers and cargos, the carrier-free PDNAs have an ultra-high or even100% drug loading. In addition, combination therapies based on PDNAs could possibly address the most intractable problems in cancer treatment, such as tumor metastasis and drug resistance. In the present review, the latest development of PDNAs for cancer treatment is overviewed. First, PDNAs are classified according to the composition of drug molecules, and the assembly mechanisms are discussed. Furthermore, the co-delivery of PDNAs for combination therapies is summarized, with special focus on the improvement of therapeutic outcomes. Finally, future prospects and challenges of PDNAs for efficient cancer therapy are spotlighted.
基金financially supported by the National Natural Science Foundation of China(No.81773656)Liaoning Revitalization Talents Program(No.XLYC1808017,China)+1 种基金Shenyang Youth Science and Technology Innovation Talents Program(No.RC190454,China)College Student Innovation and Entrepreneurship Training Program of Shenyang Pharmaceutical University(No.X202010163141,China)。
文摘The unique characteristics of the tumor microenvironment(TME)could be exploited to develop antitumor nanomedicine strategies.However,in many cases,the actual therapeutic effect is far from reaching our expectations due to the notable tumor heterogeneity.Given the amplified characteristics of TME regulated by vascular disrupting agents(VDAs),nanomedicines may achieve unexpected improved efficacy.Herein,we fabricate platelet membrane-fusogenic liposomes(PML/DP&PPa),namely“platesomes”,which actively load the hypoxia-activated pro-prodrug DMG-PR104A(DP)and physically encapsulate the photosensitizer pyropheophorbide a(PPa).Considering the different stages of tumor vascular collapse and shutdown induced by a VDA combretastatin-A4 phosphate(CA4P),PML/DP&PPa is injected 3 h after intraperitoneal administration of CA4P.First,CA4P-mediated tumor hemorrhage amplifies the enhanced permeation and retention(EPR)effect,and the platesome-biological targeting further promotes the tumor accumulation of PML/DP&PPa.Besides,CA4P-induced vascular occlusion inhibits oxygen supply,followed by photodynamic therapy-caused acute tumor hypoxia.This prolonged extreme hypoxia contributes to the complete activation of DP and then high inhibitory effect on tumor growth and metastasis.Thus,such a combining strategy of artificially-regulated TME and bio-inspired platesomes pronouncedly improves tumor drug delivery and boosts tumor hypoxia-selective activation,and provides a preferable solution to high-efficiency cancer therapy.