Impact of the Structure of Biocompatible Aliphatic Polycarbonates on siRNA Transfection Ability

Abstract

RNAi therapeutics are promising therapeutic tools that have sparked the interest of many researchers. In an effort to provide a safe alternative to PEI, we have designed a series of new guanidinium- and morpholino-functionalized biocompatible and biodegradable polycarbonate vectors. The impact of different functions (morpholino-, guanidinium-, hydrophobic groups) of the architecture (linear homopolymer to dumbbell-shape) and of the molecular weight of these copolymers on their capacity to form polyplexes and to decrease the expression of two epigenetic regulators of gene expression, HDAC7 and HDAC5, was evaluated. The use of one of these polymers combining morpholine and guanidine functions at the ratio >1 and hydrophobic trimethylene carbonate groups showed a significant decrease of mRNA and protein level in HeLa cells, similar to PEI. These results highlight the potential of polycarbonate vectors for future in vivo application as an anticancer therapy.

PEGylated and Functionalized Aliphatic Polycarbonate Polyplex Nanoparticles for Intravenous Administration of HDAC5 siRNA in Cancer Therapy

“…as well as intracellular barriers (endocytosis, endosomal escape, and siRNA release into the cytoplasm). [16][17][18][19][20] To deliver siRNA directed against HDAC5 mRNA, we have previously developed original aliphatic polycarbonate polymers, [21][22][23][24][25] grafted with guanidine and morpholine functional groups. The guanidine function, cationic at neutral pH, is necessary for both siRNA binding and interactions with the negatively charged plasma membranes.…”

“…The resulting copolymers were dried overnight under reduced pressure at room temperature. The polymer samples were characterized by SEC in THF + 2 wt % NEt 3 and 1 H-NMR in CDCl 3 to determine the macromolecular parameters, as previously described 25 . The Boc protecting groups of the guanidinium moieties were eliminated using TFA in a 5 mL stirred solution of DCM/TFA 4/1 v/v for 18 hours at room temperature.…”

“…Protocol is detailed in our previous publication. 25 In the case of a second treatment, transfection was repeated after 24 hours and cells were incubated for the remaining 24 hours. 4x10 4 transfected HCT116 cells were seeded in 24-well tissue culture plates in complete medium and were harvested at the indicated time-points.…”

Polyphosphoesters: New Trends in Synthesis and Drug Delivery Applications

“…Due to the tedious functionalization of aliphatic polyesters by amine pendant groups, few reports are dedicated to polycationic aliphatic polyesters for gene delivery . Interestingly, Frère et al recently reported on a biodegradable polycarbonate platform bearing pendant amines (morpholine and guanidine) that when incorporated in an appropriate copolymer gives particularly good transfection efficiencies …”

Poly(trimethylene carbonate)/Poly(malic acid) Amphiphilic Diblock Copolymers as Biocompatible Nanoparticles

“…[8][9][10][11][12] Additionally, PTMC featuresv aluable mechanical softness [16] that is favorably exploited, in particular,t owards the designo fc opolymers such as the thermoplasticP TMC-bpoly(l-lactide)e lastomers. [17][18][19][20][21][22][23] Other PTMC homopolymers [24][25][26][27] and copolymers associating, in particular,p oly(ethylene glycol) (PEG) [28][29][30][31][32][33][34][35][36][37][38] or poly(glutamic acid) (PGA) [39][40][41][42][43] segments [44][45][46][47] in spontaneously self-assemblingp olymeric structures, as well as otherP C-based copolymers, [48][49][50][51][52][53] have been developed over the past decade, mainly as polymer-drug conjugates, drug delivery systems, or hydrogels.…”