posted on 2020-10-21, 15:12authored byAna I. Carbajo-Gordillo, José L. Jiménez Blanco, Juan M. Benito, Hugo Lana, Gema Marcelo, Christophe Di Giorgio, Cédric Przybylski, Hiroshi Hinou, Valentín Ceña, Carmen Ortiz Mellet, Francisco Mendicuti, Conchita Tros de Ilarduya, José M. García Fernández
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.