Investigating the crucial roles of aliphatic tails in disulfide bond-linked docetaxel prodrug nanoassemblies

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.

“Yin-Yang philosophy”for the design of anticancer drug delivery nanoparticles

Understanding the in vivo transport process provides guidelines for designing ideal nanoparticles(NPs)with higher efficacy and fewer off-target effects.Many factors,such as particle size,morphology,surface potential,structural stability,and etc.,may influence the delivering process of NPs due to the existence of various physiological barriers within the body.Herein,we summarise the distinct influences of NP physicochemical properties on the four consecutive in vivo transport steps:(1)navigating with bloodstream within blood vessels,(2)transport across vasculature walls into tumour tissues,(3)intratumoural transport through the interstitial space,and(4)cellular uptake&intracellular delivery by cancerous cells.We found that the philosophy behind the current consensus for NP design has certain similarities to the“Yin-Yang”theory in traditional Chinese culture.Almost all physicochemical properties,regardless of big or small sizes,long or short length,positive or negative zeta potentials,are double-edged swords.The balance of potential benefits and side effects,drug selectivity and accessibility should be fully considered when optimising particle design,similar to the“Yin-Yang harmony”.This paper presents a comprehensive review of the advancements in NPs research,focusing on their distinct features in tumour targeting,drug delivery,and cell uptake.Additionally,it deliberates on future developmental trends and potential obstacles,thereby aiming to uncover the ways these characteristics influence the NPs’biological activity and provide theoretical guidance for the targeted delivery of NPs.