Dimeric prodrug self-assembly nanoparticles (DPS NPs) present promising avenues for chemotherapeutic delivery, yet optimizing the linker design for effective SN38 delivery remains challenging. We developed various SN38 dimeric prodrugs with differing linker lengths to explore how linker length impacts DPS NP performance. Our study reveals that linker length critically affects the nanoparticles assembly stability and activation efficiency. Specifically, too short linkers compromise assembly stability and lead to premature drug activation in the bloodstream, raising safety concerns. Conversely, too long linkers hinder both assembly stability and activation efficiency within tumor cells, diminishing anti-tumor effectiveness. The optimal linker (C12) achieved the best balance, ensuring robust assembly stability and high activation efficiency, thereby enhancing anti-tumor efficacy while maintaining a favorable safety profile. This work underscores the significance of linker length in designing effective DPS NPs for cancer treatment.
Liu Fang,Zou Lingyun,Chen Yongcheng,Liu Zuolong,Huang Yue,Jin Qiao,Ji Jian
Biofilm-associated bacterial infection brings serious threats to global public health owing to serious antibiotic resistance. It is urgently needed to develop innovative strategies to combat biofilm-associated bacterial infections. Polymyxins stand out as the last line of defense against Gram-negative bacteria. However, serious nephrotoxicity of polymyxins severely limits their clinical utility. Herein, a hypoxia-responsive liposome is designed as the nanocarrier of polymyxin B (PMB) to combat biofilms developed by Gram-negative bacteria. A metronidazole modified lipid (hypoxia-responsive lipid (HRLipid)) is synthesized to fabricate hypoxia-responsive liposomes (HRLip). PMB loaded hypoxia-responsive liposomes (HRL-PMB) is then prepared to mitigate the nephrotoxicity of PMB while preserving its excellent bactericidal activity. HRL-PMB shows very low hemolysis and cytotoxicity due to liposomal encapsulation of PMB. PMB can be readily released from HRL-PMB in response to hypoxic biofilm microenvironment, exerting its bactericidal activity to realize biofilm eradication. The excellent in vivo antibiofilm ability of HRL-PMB is confirmed by a Pseudomonas aeruginosa infected zebrafish model and a P. aeruginosa pneumonia infection model. Meanwhile, HRL-PMB can greatly reduce the nephrotoxicity of PMB after intravenous injection. The hypoxia-sensitive liposomes held great promise to improve the biosafety of highly toxic antibiotics while preserving their intrinsic bactericidal ability, which may provide an innovative strategy for combating biofilm-associated infections.
Mengru Ding,Lingling Ni,Ying Zheng,Bao Wang,Chengtao Yu,Guorong Shan,Yongzhong Bao,Junfeng Liu,Pengju Pan
Long-spaced aliphatic polyesters are typical sustainable polyethylene (PE)-like polymers. However, the presence of a low amount of ester groups can exert a profound effect on the crystalline structure of such PE-like polymers. Herein, we synthesized a series of long-spaced aliphatic polyesters bearing two proximate ester groups from ethylene glycol (EG) and n-methylene diacids (n = 9–18) and investigated their polymorphic crystallization and phase transitions. We find that the EG-based polyesters exhibit unique crystal polymorphism and phase transition behaviors. They can form a metastable hexagonal phase (form II) with nontilted, extended chain conformations at low temperatures or during rapid cooling but adopt the thermally stable orthorhombic phase (form I) with tilted chain packing at high temperatures or under slow cooling. Form I demonstrates a more densely packed chain structure and displays distinct mechanical properties compared to form II. The metastable hexagonal phase can transform into an orthorhombic phase during heating through a melt-recrystallization mechanism. This study advances the current understanding of the multiphase crystallization of PE-like long-spaced polyesters.
Mengen Zhang,Ruijia Wang,Tinghao Jia,Congjing Ren,Jingdai Wang,Yongrong Yang,Yao Yang
A molecular-level understanding of the ion cluster morphology is crucial to designing the structure and enhancing the properties of random polyethylene ionomer. Here, we report that the strategic addition of aliphatic disodium salt has a pronounced effect on the mechanical properties and nanoscale morphology. With the addition of various aliphatic disodium salts, both the tensile strength and Young’s modulus are significantly increased. By comparing the results of atomistic molecular dynamics simulations with experimental characterization data, the ionic cluster nanoscale morphology varies with different chain-length disodium salts, while maintaining the crystallization of the polyethylene matrix. The alkyl disodium salts with relatively short alkyl chains (C12) bridge between clusters by anchoring to two different clusters, helping to redistribute the clusters within the polymer matrix and providing additional cross-link strength. The cluster morphological evolution during stretching was simulated, and its relation to mechanical properties is comprehensively discussed. This, in turn, unlocks the potential for structural regulation at the nanoscale by additive manufacturing to enhance the performance.
危险品化学品经营许可证（带存储）