Click Synthesis of Size- and Shape-Tunable Star Polymers with Functional Macrocyclic Cores for Synergistic DNA Complexation and Delivery

Abstract

The architectural perfection and multivalency of dendrimers have made them useful for biodelivery via peripheral functionalization and the adjustment of dendrimer generations. Modulation of the core-forming and internal matrix-forming structures offers virtually unlimited opportunities for further optimization, but only in a few cases this has been made compatible with strict diastereomeric purity over molecularly diverse series, low toxicity, and limited synthetic effort. Fully regular star polymers built on biocompatible macrocyclic platforms, such as hyperbranched cyclodextrins, offer advantages in terms of facile synthesis and flexible compositions, but core elaboration in terms of shape and function becomes problematic. Here we report the synthesis and characterization of star polymers consisting of functional trehalose-based macrocyclic cores (cyclotrehalans, CTs) and aminothiourea dendron arms, which can be efficiently synthesized from sequential click reactions of orthogonal monomers, display no cytotoxicity, and efficiently complex and deliver plasmid DNA in vitro and in vivo. When compared with some commercial cationic dendrimers or polymers, the new CT-scaffolded star polymers show better transfection efficiencies in several cell lines and structure-dependent cell selectivity patterns. Notably, the CT core could be predefined to exert Zn(II) complexing or molecular inclusion capabilities, which has been exploited to synergistically boost cell transfection by orders of magnitude and modulate the organ tropism in vivo.

Trifaceted Mickey Mouse Amphiphiles for Programmable Self‐Assembly, DNA Complexation and Organ‐Selective Gene Delivery

“…However, the transfection efficiency monotonically decreased with the N/P value, suggesting that formation of the external compact shell results in very stable CTplexes from which release of the pDNA cargo intracellularly takes place at a lower rate. The situation is analogous to that encountered for CTplexes obtained from dendronized CT3‐centred star polymers [12] . The irregular morula and globular shaped CTplexes formulated from 8 and 9 showed comparatively poorer transfection efficiencies.…”

“…Homogeneous functionalization of the CT2 (cyclotetrasaccharide) and CT3 (cyclohexasaccharide) members was put at work to access highly symmetrical polycationic starshape polymers (Figure 1B) that showed high gene delivery efficiencies. [12] Interestingly, CTs can potentially be constructed from differently functionalized building blocks, then resulting in anisotropically-faceted architectures. This notion was first realized for the simplest CT2 core: perfect Janus MNPs featuring cationic (C) and lipophilic (L) halves were elaborated that formed multilamellar transfectious nanocomplexes (CTplexes) with plasmid DNA (pDNA) (Figure 2A).…”

“…Differently from CDs, which are intrinsically dissymmetric Janus molecules, CTs portray as many faces as the number of constitutive α,α’‐trehalose units, all of which bear six secondary hydroxyls and are chemically identical in the canonical CT representatives. Homogeneous functionalization of the CT2 (cyclotetrasaccharide) and CT3 (cyclohexasaccharide) members was put at work to access highly symmetrical polycationic star‐shape polymers (Figure 1B) that showed high gene delivery efficiencies [12] …”

“…Homogeneous functionalization of the CT2 (cyclotetrasaccharide) and CT3 (cyclohexasaccharide) members was put at work to access highly symmetrical polycationic star‐shape polymers (Figure 1 B) that showed high gene delivery efficiencies. [12] …”

Cyclodextrin-Based Functional Glyconanomaterials

“…Most nonviral nucleid acid carriers (vectors) reported are polymeric, conformationally undefined or complex nanoparticulate materials [85]. In the last decade, however, multivalent polycations based on molecular systems emerged as a promising alternative [86][87][88][89][90][91][92][93][94][95][96]. Polycationic cyclodextrins have become the iconic representatives in this category [5,[97][98][99][100][101][102][103][104].…”