Multifunctional Cationic PeptoStars as siRNA Carrier: Influence of Architecture and Histidine Modification on Knockdown Potential

Abstract

RNA interference provides enormous potential for the treatment of several diseases, including cancer. Nevertheless, successful therapies based on siRNA require overcoming various challenges, such as poor pharmacokinetic characteristics of the small RNA molecule and inefficient cytosolic accumulation. In this respect, the development of functional siRNA carrier systems is a major task in biomedical research. To provide such a desired system, the synthesis of 3‐arm and 6‐arm PeptoStars is aimed for. The different branched polypept(o)idic architectures share a stealth‐like polysarcosine corona for efficient shielding and a multifunctional polylysine core, which can be independently varied in size and functionality for siRNA complexation‐, transport and intra cellular release. The special feature of star‐like polypept(o)ides is in their uniform small size (<20 nm) and a core–shell structure, which implies a high stability and stealth‐like properties and thus, they may combine long circulation times and a deep penetration of cancerous tissue. Initial toxicity and complement studies demonstrate well tolerated cationic PeptoStars with high complexation capability toward siRNA (N/P ratio up to 3:1), which can lead to potent RNAi for optimized systems. Here, the synthetic development of 3‐arm and 6‐arm polypept(o)idic star polymers, their modification with endosomolytic moieties, and first in vitro insights on RNA interference are reported on.

Versatile, Multifunctional Block Copolymers for the Self-Assembly of Well-Defined, Nontoxic pDNA Polyplexes

“…Thus, it becomes possible to stabilize polyplexes reversibly by reducing cross-linking of the polyplex. − This requires, however, the synthesis of a triblock copolymer, which consists (i) of a well water-soluble, stealthlike block, a (ii) reversibly cross-linkable block to stabilize the transport form, and a (iii) polycationic block to complex the polyanionic oligonucleotide in the form of a polyplex (see Scheme ). Such structures have been made successfully based on polypept­(o)­ids. ,, We describe here in this paper the synthesis of triblock copolymers of the same functionality (stealthlike, reversibly cross-linkable, based on disulfide formation, and polycationic) by reversible addition–fragmentation chain transfer (RAFT) polymerization of methacrylate-based monomers. Also, we search for orthogonally reactive units to build them up.…”

An Inspection into Multifarious Ways to Synthesize Poly(Amino Acid)s

“…[58] Barz and co-workers and Heise and co-workers synthesized various star-like PAAs by multifunctional initiators. [59,60] The star-like PAAs served as nanocarriers in mucosal drug delivery [61] and delivery of small interfering RNAs (siRNAs) [59] and DNAs. [62,63] Vicent and co-workers reported star-shaped polyglutamates, which self-assembled softly into nanostructures with applicability in drug delivery.…”

The generation of stabilized supramolecular nanorods from star-shaped polyglutamates

“…18 Some studies attempted to combine BTA-cores with poly-amino acid derivatives; however, BTA played the role of a multifunctional core rather than supramolecular motif in all cases. [18][19][20] Besenius pioneered a method of charge screening for small BTA-based molecules bearing ionizable groups with low molecular weight salts, achieving control for up to nine charges for Newkome dendron-decorated molecules. 21 We hypothesized that replacing Newkome dendrons with small PGA chains should allow the formation of stable structures that can self-assemble in water and other physiological solutions.…”