Cytosolic Delivery of Single-Chain Polymer Nanoparticles

Abstract

Cytosolic delivery of therapeutic agents is key to improving their efficacy, as the therapeutics are primarily active in specific organelles. Single-chain polymer nanoparticles (SCNPs) are a promising nanocarrier platform in biomedical applications due to their unique size range of 5–20 nm, modularity, and ease of functionalization. However, cytosolic delivery of SCNPs remains challenging. Here, we report the synthesis of active ester-functional SCNPs of approximately 10 nm via intramolecular thiol-Michael addition cross-linking and their functionalization with increasing amounts of tertiary amines 0 to 60 mol % to obtain SCNPs with increasing positive surface charges. No significant cytotoxicity was detected in bEND.3 cells for the SCNPs, except when SCNPs with high amounts of tertiary amines were incubated over prolonged periods of time at high concentrations. Cellular uptake of the SCNPs was analyzed, presenting different uptake behavior depending on the degree of functionalization. Confocal microscopy revealed successful cytosolic delivery of SCNPs with high degrees of functionalization (45%, 60%), while SCNPs with low amounts (0% to 30%) of tertiary amines showed high degrees of colocalization with lysosomes. This work presents a strategy to direct the intracellular location of SCNPs by controlled surface modification to improve intracellular targeting for biomedical applications.

Self-Assembled Amphiphilic Fluorinated Random Copolymers for the Encapsulation and Release of the Hydrophobic Combretastatin A-4 Drug

“…The size of SCNPs (generally <10 nm in diameter) is significantly smaller than that of conventional polymer nanocarriers and more akin to that of globular proteins or small viruses. The study of how this may affect the bioavailability of the drug encapsulated in SCNP carriers is still in the early stages but points to their increased cellular uptake compared to larger nanoparticles [26][27][28][29][30]. The successful encapsulation of small hydrophobic molecules has been carried out in covalently crosslinked SCNPs [26,31,32] as well as in self-folding amphiphilic SCNPs [33,34].…”

Preparation of AIE Functional Single‐Chain Polymer Nanoparticles and Their Application in H2O2 Detection through Intermolecular Heavy‐Atom Effect

“…Single-chain polymer nanoparticles (SCNPs) are a charming kind of material due to their small size, modularity, and easy functionalization. [1] And they are prepared by an interesting method-folding a single linear polymer chain, [2][3][4] having potential applications in nanomedicine, [5,6] catalysis, [7,8] and sensing. [9,10] Owing to chain collapse, the formed SCNPs pockets provide a unique internal environment for the attachment of active species, such as drugs, catalysts, or dyes.…”

Influence of structural dynamics on cell uptake investigated with single-chain polymeric nanoparticles

“…SCPNs are synthesized by performing intra-chain crosslinking reactions, where loops are introduced to the precursor polymer chains for compaction. 34,35 Recent researches [36][37][38][39][40] have demonstrated SCPNs' promise for cytosolic drug delivery but the fundamental study on the role of structural dynamics in cellular interactions to the best of our knowledge has been performed only via computational tools 20,41,42 . We have taken advantage of the recent advancement in the control and characterization of SCPNs 43,44,45 to produce nanoparticles with different degrees of structural dynamics.…”