A Long‐Circulating Vector for Aptamers Based upon Polyphosphodiester‐Backboned Molecular Brushes

Abstract

Aptamers face challenges for use outside the ideal conditions in which they are developed. These difficulties are most palpable in vivo due to nuclease activities, rapid clearance, and off-target binding. Herein, we demonstrate that a polyphosphodiester-backboned molecular brush can suppress enzymatic digestion, reduce non-specific cell uptake, enable long blood circulation, and rescue the bioactivity of a conjugated aptamer in vivo. The backbone along with the aptamer is assembled via solid-phase synthesis, followed by installation of poly(ethylene glycol) (PEG) side chains using a two-step process with near-quantitative efficiency. The synthesis allows for precise control over polymer size and architecture. Consisting entirely of building blocks that are generally recognized as safe for therapeutics, this novel molecular brush is expected to provide a highly translatable route for aptamer-based therapeutics.

A mechanistic study on the cellular uptake, intracellular trafficking, and antisense gene regulation of bottlebrush polymer-conjugated oligonucleotides

“…Indeed, an anionic form of pacDNA with a negatively charged, hydrophilic backbone undergoes very limited cellular uptake, similar to that of free DNA. 40 Together, these data identify SR-A-mediated endocytosis (both clathrin-and caveolae-dependent pathways) and macropinocytosis as the main mechanisms for the uptake of pacDNA by NCI-H358 cells.…”

Cooperatively designed aptamer-PROTACs for spatioselective degradation of nucleocytoplasmic shuttling protein for enhanced combinational therapy

“…The critical difference between traditional small-molecule PROTACs and PS-ApTCs is the aptamer targeting warhead enables PS-ApTCs to specically recognize target cancer cells, while PS modication enhances the stability of PS-ApTCs from nucleasemediated degradation. 16 These features are generally considered to be a requirement for improving the therapeutic index. 17,18 To evaluate this experimentally, we rst chose the NCL as the POI, and AS1411 as the NCL-binding domain (Fig.…”