PH-Response Of Nanocarriers Of Tertiary Amine Modified Cyclic Acetal-functionalized Polymers For Drug Delivery System

Recently, the pH sensitive polymers have attracted much attention in the field of cancer treatment. In this paper, cyclic acetal-functionalized comonomer, 2,4,6-trimethoxybenzylidene-1,1,1-tris(hydroxymethyl) ethane methacrylate(TTMA) and 2-(diisopropylamino) ethyl methacrylate(DPA) were used to synthesize pH-sensitive amphiphilic copolymers(mPEG-b-P(TTMA-co-DPA)). The nanosized assemblies of mPEG-b-P(TTMA-co-DPA) were fabricated and the drug and siRNA delivery behaviors were also evaluated.Firstly, a series of amphiphilic copolymers with different amount of DPA units, methoxy poly(ethylene glycol)-b-poly((2,4,6-trimethoxybenzylidene-1,1,1-tris(hydroxymethyl) ethane methacrylate)-co-2-(diisopropylamino) ethyl methacrylate)(mPEG5k-b-P(TTMA-co-DPA)5k)(PE5kTD5k-0~3), were synthesized by reversible addition fragmentation chain transfer(RAFT) copolymerization of TTMA and DPA with methoxy poly(ethylene glycol) modified by 2-(dodecylthiocarbonothioylthio)-2-methylpropionic acid as the RAFT agent. The molecular structures and chemical compositions were confirmed by 1H-NMR, FT-IR and GPC. All the copolymers could be assembled into stable nanoparticles in PB buffer(pH 7.4) by nanoprecipitation, which displayed low critical micelle concentration(CMC, 0.71~0.97 ?g/m L). Besides, we found that the addition of different amount of DPA segments showed two opposite effects on the hydrolysis rate of the CBAs groups, decreasing the hydrolysis rate at a low DPA content(PE5k TD5k-1,5.8%) while increasing the hydrolysis rate at a higher DPA content(PE5k TD5k-3,24.0%). The swelling and disintegration of nanoparticles in the acid condition facilitated the release of the payloaded drug releasing. The drug release rates from the four kinds of nanoparticles followed the general order of the hydrolysis rate: PE5kTD5k-3 > PE5kTD5k-0 ? PE5kTD5k-2 > PE5kTD5k-1. Toxicity test revealed that all the blank copolymer nanoparticles exhibited low cytotoxicity, whereas the DOX-loaded PE5kTD5k-3 nanoparticles demonstrated more efficient growth inhibition toward Hep G-2 cells than any other nanoparticles.Secondly, we systhesized a series of copolymers mPEG2k-b-P(TTMA-co-DPA)10k(PE2kTD10k-I~IV) with different feed ratios of TTMA and DPA by RAFT polymerization. siRNA were successfully encapsulated into nanocapsules of PE2kTD10 k by double emulsious-solvent evaporation technique. The results indicated that the nanocapsules could encapsulate siRNA with high loading efficiency(about 93%), uniform size and good stability. The influence of PDPA segments on the hydrolysis of CBAs also displayed in two different ways, decreaseing the hydrolysis rate at a low DPA content while facilitating the hydrolysis at a higher DPA content. Toxicity test revealed that all the blank copolymer nanocapsules exhibited relatively lower cytotoxicity, whereas the gene silencing efficiency needs to be promoted.