Achieving Safe and Highly Efficient Epidermal Growth Factor Receptor Silencing in Cervical Carcinoma by Cationic Degradable Hyperbranched Polymers

Abstract

Novel cationic hyperbranched polymers were prepared from 2-aminoethyl methacrylate (AEMA) and di(ethylene glycol) methyl ether methacrylate (DEGMA) via the reversible addition−fragmentation chain transfer (RAFT) polymerization for siRNA delivery. Non-degradable and acid-degradable hyperbranched polymers were synthesized using N,N′-methylenebis(acrylamide) (MBAm) and 2,2dimethacroyloxy-1-ethoxypropane (DEP) cross-linkers, respectively. Both types of polymers were capable of forming very stable nanosized polyplexes with siRNA. Epidermal growth factor receptor (EGFR) silencing of 95% was achieved with the acid degradable cationic hyperbranched polymer, and no significant cytotoxicity was observed. Our results confirmed the high potency of using such hyperbranched polymers for the efficient protection and delivery of siRNA.

Tumor Microenvironment-Regulated Redox Responsive Cationic Galactose-Based Hyperbranched Polymers for siRNA Delivery

“…The results observed with HRRP 2 polyplexes were quite remarkable, considering the lower toxicity of these HRRP polymers as compared to Lipofectamine. Furthermore, HRRP 2 demonstrated to be a superior siRNA carrier (85% EGFR silencing) in comparison to our previously reported acid degradable cationic hyperbranched galactose-based polymer (60% EGFR silencing) with similar cell viability …”

“…The redox-responsive hyperbranched and cationic glycopolymers were synthesized by minor adjustments of our previously reported methods. ,, In brief, 0.5 g LAEMA (1.06 mmol) and 88 mg AEMA (0.53 mmol) were dissolved into 1.5 mL doubly-distilled water (DI H 2 O) and mixed with 1.65 mL methanol solution which contained pre-dissolved 23 mg BMAC (79.74 μmol), 12 mg CTP (43.01 μmol), and 4 mg ACVA (14.28 μmol). The mixture was degassed for 30 minutes and then polymerization was conducted at 67 °C for 24 h. The reaction was quenched by using liquid nitrogen and the polymers were precipitated in acetone and purified by washing three times with methanol.…”

“…Another advantage of having a hyperbranched structure is towards the facile preparation of “smart” and responsive siRNA delivery systems. Biocompatible and efficient in vitro siRNA carriers were easily prepared by utilizing an acid cleavable cross-linker. , Redox-responsive carriers had been prepared for gene therapy; thus, in this study, we optimized, modulated, and prepared a redox-responsive galactose-based system and investigated its potency in siRNA delivery.…”

Synthesis and functionalization of hyperbranched polymers for targeted drug delivery

“…Like dendrimers, HBPs form cavities that can be used to encapsulate cargos of different sizes [118] including small chemotherapeutic drugs such as DOX, [119,120] camptothecin (CPT), [121,122] cisplatin, [123][124][125] [127][128][129][130] and siRNA [131][132][133] form complexes with unimolecular HBPs such as branched poly(ethylene imine) (PEI) [134] by electrostatic interactions. Tuning the structure of HBPs permits to control the strength of the interaction between gene and carrier by modulating the charge density at its surface, adjusting its molecular weight, and preparing different molecular structures.…”

“…doxorubicin (DOX) and paclitaxel (PTX) for cancer treatment, and radioisotopes, e.g. 99m Tc, 131 I, and 125 I, for diagnostic purposes. Furthermore, the high density of functional groups at the periphery of HBPs can be exploited to introduce functionalities on HBPs.…”