Self-Amplified Cascade Degradation and Oxidative Stress Via Rational pH Regulation of Oxidation-Responsive Poly(ferrocene) Aggregates.

Precise activation of polymer nanoparticles at lesion sites is crucial to achieve favorable therapeutic efficacy. However, conventional endogenous stimuli-responsive polymer nanoparticles probably suffer from few triggers to stimulate the polymer degradation and subsequent functions. Here, we describe oxidation-responsive poly(ferrocene) amphiphiles containing phenylboronic acid ester and ferrocene as the repeating backbone units. Upon triggering by hydrogen peroxide inside the tumor cells, the phenylboronic acid ester bonds are broken and poly(ferrocene) units are degraded to afford free ferrocene and noticeable hydroxide ions. The released hydroxide ions can immediately improve the pH value within the poly(ferrocene) aggregates, and the degradation rate of the phenylboronic acid ester backbone is further promoted by the upregulated pH; thereupon, the accelerated degradation can release much more additional hydroxide ions to improve the pH, thus achieving a positive self-amplified cascade degradation of poly(ferrocene) aggregates accompanied by oxidative stress boosting and efficient cargo release. Specifically, the poly(ferrocene) aggregates can be degraded up to ∼90% within 12 h when triggered by H2O2, while ferrocene-free control nanoparticles are degraded by only 30% within 12 days. In addition, the maleimide moieties tethered in the hydrophilic corona can capture blood albumin to form an albumin-rich protein corona and significantly improve favorable tumor accumulation. The current oxidation-responsive poly(ferrocene) amphiphiles can efficiently inhibit tumors in vitro and in vivo. This work provides a proof-of-concept paradigm for self-amplified polymer degradation and concurrent oxidative stress, which is promising in actively regulated precision medicine.

Coordinating External and Built-In Triggers for Tunable Degradation of Polymeric Nanoparticles via Cycle Amplification.

The selective activation of nanovectors in pathological tissues is of crucial importance to achieve optimized therapeutic outcomes. However, conventional stimuli-responsive nanovectors lack sufficient sensitivity because of the slight difference between pathological and normal tissues. To this end, the development of nanovectors capable of responding to weak pathological stimuli is of increasing interest. Herein, we report the fabrication of amphiphilic polyurethane nanoparticles containing both external and built-in triggers. The activation of external triggers leads to the liberation of highly reactive primary amines, which subsequently activates the built-in triggers with the release of more primary amines in a positive feedback manner, thereby triggering the degradation of micellar nanoparticles in a cycle amplification model. The generality and versatility of the cycle amplification concept have been successfully verified using three different triggers including reductive milieu, light irradiation, and esterase. We demonstrate that these stimuli-responsive nanoparticles show self-propagating degradation performance even in the presence of trace amounts of external stimuli. Moreover, we confirm that the esterase-responsive nanoparticles can discriminate cancer cells from normal ones by amplifying the esterase stimulus that is overexpressed in cancer cells, thereby enabling the selective release of encapsulated payloads and killing cancer cells. This work presents a robust strategy to fabricate stimuli-responsive nanocarriers with highly sensitive property toward external stimuli, showing promising applications in cancer therapy with minimized side effects.

Synthesis of Polypeptides with High-Fidelity Terminal Functionalities under NCA Monomer-Starved Conditions.

Controlled polypeptide synthesis via α-amino acid N-carboxylic anhydride (NCA) polymerization using conventional primary amine initiators encounters two major obstacles: (i) normal amine mechanism (NAM) and activated monomer mechanism (AMM) coexist due to amine basicity and nucleophilicity and (ii) NCA is notoriously sensitive towards moisture and heat and unstable upon storage. We serendipitously discover that N-phenoxycarbonyl-functionalized α-amino acid (NPCA), a latent NCA precursor, could be polymerized solely based on NAM with high initiating efficiency by using primary amine hydrochloride as an initiator. The polymerization affords well-defined polypeptides with narrow polydispersity and high-fidelity terminal functionalities, as revealed by the clean set of MALDI-TOF MS patterns. We further demonstrate successful syntheses of random and block copolypeptides, even under open-vessel conditions. Overall, the integration of moisture-insensitive and air-tolerant NPCA precursors with stable primary amine hydrochloride initiators represents a general strategy for controlled synthesis of high-fidelity polypeptides with sophisticated functions.