Modulated Fragmentation of Proapoptotic Peptide Nanoparticles Regulates Cytotoxicity

Abstract

Peptides perform a diverse range of physiologically important functions. The formulation of nanoparticles directly from functional peptides would therefore offer a versatile and robust platform to produce highly functional therapeutics. Herein, we engineered proapoptotic peptide nanoparticles from mitochondria-disrupting KLAK peptides using a template-assisted approach. The nanoparticles were designed to disassemble into free native peptides via the traceless cleavage of disulfide-based cross-linkers. Furthermore, the cytotoxicity of the nanoparticles was tuned by controlling the kinetics of disulfide bond cleavage, and the rate of regeneration of the native peptide from the precursor species. In addition, a small molecule drug (i.e., doxorubicin hydrochloride) was loaded into the nanoparticles to confer synergistic cytotoxic activity, further highlighting the potential application of KLAK particles in therapeutic delivery.

Self‐Assembled Metal–Phenolic Networks on Emulsions as Low‐Fouling and pH‐Responsive Particles

“…[1,2] Selfassembly, a process that allows molecular species to arrange into complex architectures, has enabled a range of nanomaterials to be devised for drug delivery, including liposomes, [3] porphysomes, [4] and polymeric micelles. [5] By exploiting self-assembly, reversibility can be engineered into self-assembled structures where the materials can be designed to respond to external (temperature, magnetic field, light, and ultrasound) or endogenous (pH, enzymatic reaction, glucose, and redox environment) stimuli, [6][7][8][9][10][11][12] thereby allowing for the release of therapeutic drugs. Self-assembled nanomaterials are therefore considered promising nanosystems to deliver drugs and biological macromolecules for therapeutic applications.…”

Reduction‐Triggered Transformation of Disulfide‐Containing Micelles at Chemically Tunable Rates

“…Firstly, four types of reduction‐sensitive monomers with varying disulfide triggers, 2,2′‐dithiobis(ethoxycarbonyl) (SSE) and 4,4′‐dithiobis(benzyloxy‐carbonyl) (SSB), and self‐immolative linkers of different lengths were designed, aiming to achieve rate‐tunable disulfide cleavage and self‐immolative degradation (see Schemes S1 and S2 for chemical structures, and Figures S1–S4 in the Supporting Information for more details) . As a control for SSEM (SSE‐based methacrylate monomer), an SSEMO monomer containing a carbonate instead of carbamate linker was also designed (see Scheme S3a and Figure S1).…”

Emerging Applications of Fluorogenic and Non‐fluorogenic Bifunctional Linkers

“…e) Proapoptotic peptide nanoparticles fabricated from mitochondria‐disrupting KLAK peptides functionalized with disulfide‐containing self‐immolative linkers, followed by cross‐linking with eight‐armed PEG‐SH. Intact KLAK peptides are released upon applying a reductive trigger . f) Cell‐penetrating poly(disulfide)s (CPDs) mediate the intracellular uptake of protein conjugates, which undergo self‐immolative degradation and release native proteins …”

“…Caruso et al . reported the fabrication of nanoparticles directly from mitochondria‐disrupting KLAK peptides by using self‐immolative hetero‐bifunctional linkers (NDBC and NDEC) to cross‐link peptides and eight‐armed PEG‐SH.…”

“…Intact KLAK peptides are released upon applying areductive trigger. [47] f) Cell-penetrating poly(disulfide)s (CPDs)m ediate the intracellular uptake of protein conjugates, whichu ndergoself-immolative degradation and releasen ative proteins. [48] Caruso et al [47] reported the fabrication of nanoparticles directly from mitochondria-disrupting KLAK peptides by using self-immolative hetero-bifunctionall inkers (NDBC and NDEC) to cross-link peptides and eight-armed PEG-SH.T hese nanoparticles disassemble into native KLAK peptides through disulfide cleavage and self-immolative cascaded egradation (Figure 5e).…”