ABC-type triblock copolymers are a rising platform especially for oligonucleotide delivery as they offer an additional functionality besides the anyhow needed functions of shielding and... Show moreABC-type triblock copolymers are a rising platform especially for oligonucleotide delivery as they offer an additional functionality besides the anyhow needed functions of shielding and complexation. The authors present a polypept(o)ide-based triblock copolymer synthesized by amine-initiated ring-opening polymerization (ROP) of N-carboxyanhydrides (NCAs), comprising a shielding block A of polysarcosine (pSar), a poly(S-ethylsulfonyl-l-cystein) (pCys(SO2 Et)) block B for bioreversible and chemo-selective cross-linking and a poly(l-lysine) (pLys) block C for complexation to construct polyion complex (PIC) micelles as vehicle for small interfering RNA (siRNA) delivery. The self-assembly behavior of ABC-type triblocks is investigated to derive correlations between block lengths of the polymer and PIC micelle structure, showing an enormous effect of the β-sheet forming pCys(SO2 Et) block. Moreover, the block enables the introduction of disulfide cross-links by reaction with multifunctional thiols to increase stability against dilution. The right content of the additional block leads to well-defined cross-linked 50-60 nm PIC micelles purified from production impurities and determinable siRNA loading. These PIC micelles can deliver functional siRNA into Neuro2A and KB cells evaluated by cellular uptake and specific gene knockdown assays. Show less
Chen, X.; Jin, R.; Jiang, Q.; Bi, Q.; He, T.; Song, X.; ... ; Nie, Y. 2021
The tumor hypoxic microenvironment not only induces genetic and epigenetic changes in tumor cells, immature vessels formation for oxygen demand, but also compromises the efficiency of therapeutic... Show moreThe tumor hypoxic microenvironment not only induces genetic and epigenetic changes in tumor cells, immature vessels formation for oxygen demand, but also compromises the efficiency of therapeutic interventions. On the other hand, conventional therapeutic approaches which kill tumor cells or destroy tumor blood vessels to block nutrition and oxygen supply usually facilitate even harsher microenvironment. Thus, simultaneously relieving the strained response of tumor cells and blood vessels represents a promising strategy to reverse the adverse tumor hypoxic microenvironment. In the present study, an integrated amphiphilic system (RSCD) is designed based on Angiotensin II receptor blocker candesartan for siRNA delivery against the hypoxia-inducible factor-1 alpha (HIF-1α), aiming at both vascular and cellular "relaxation" to reconstruct a tumor normoxic microenvironment. Both in vitro and in vivo studies have confirmed that the hypoxia-inducible HIF-1α expression is down-regulated by 70% and vascular growth is inhibited by 60%. The "relaxation" therapy enables neovascularization with more complete and organized structures to obviously increase the oxygen level inside tumor, which results in a 50% growth inhibition. Moreover, reconstruction of tumor microenvironment enhances tumor-targeted drug delivery, and significantly improves the chemotherapeutic and photodynamic anticancer treatments. Show less
