Star-Shaped Cationic Polymers by Atom Transfer Radical Polymerization from β-Cyclodextrin Cores for Nonviral Gene Delivery

Abstract

Cationic polymers with low cytotoxicity and high transfection efficiency have attracted considerable attention as nonviral carriers for gene delivery. Herein, well-defined and star-shaped CDPD consisting of beta-CD cores and P(DMAEMA) arms, and CDPDPE consisting of CDPD and P(PEGEEMA) end blocks (where CD = cyclodextrin, P(DMAEMA) = poly(2-(dimethylamino)ethyl methacrylate), P(PEGEEMA) = poly(poly(ethylene glycol)ethyl ether methacrylate)) for gene delivery were prepared via atom transfer radical polymerization (ATRP) from the bromoisobutyryl-terminated beta-CD core. The CDPD and CDPDPE exhibit good ability to condense plasmid DNA (pDNA) into 100-200 nm size nanoparticles with positive zeta potentials of 25-40 mV at nitrogen/phosphate (N/P) ratios of 10 or higher. CDPD and CDPDPE exhibit much lower cytotoxicity and higher gene transfection efficiency than high molecular weight P(DMAEMA) homopolymers. A comparison of the transfection efficiencies between CDPD and P(DMAEMA) homopolymer indicates that the unique star-shaped architecture involving the CD core can enhance the gene transfection efficiency. In addition to reducing cytotoxicity, the introduction of a biocompatible P(PEGEEMA) end block to the P(DMAEMA) arms in CDPDPE can further enhance the gene transfection efficiency.

Polycationic star polymers with hyperbranched cores for gene delivery

“…Low molar mass compounds, such as pentaerythritol [11] and its derivative [12], tris(α-bromoisobutyryl) N-methyl triethanolamine [13] and various calixarene derivatives [14,15] or functionalized cyclic saccharides [16][17][18], have been used. Tam et al grafted DMAEMA onto four arm poly(ethylene oxide) [19,20] or onto C 60 -fullerene [21].…”

“…The condensation of DNA is more efficient for PDMAEMA star polymers in comparison to linear analogues [9,16]. The dense molecular star structure and the higher number of functional groups for a given degree of polymerization compared to linear polymers used in polyplexes have improved the effectiveness of stars for DNA complexation [7,8].…”

“…Based on verified experimental data, the molar mass, the functionality of stars, their conformation in water and culture media solution, and the charge density are expected to exert significant influences on transfection efficiency and should be examined very carefully. Even the molar masses of the stars, which are basic characteristics, are frequently only estimated based upon GPC calibrated with linear polymers [7,9,16,32]. Thus, the absolute molar mass and dispersity data are hardly available.…”

“…The number and lengths of star arms are expected to be essential for transfection. However, their influence remains a subject of discussion, as transfection efficiency has been reported to both decrease [7] and increase with increasing arm length [16].…”

“…It is known that transfection efficiency increases with the polymer concentration, but this increase is accompanied by a decrease in cell viability [7,8,16]. In general, cytotoxicity increases with the increasing molar mass of the polycationic polymer.…”