Nitric oxide-containing supramolecular polypeptide nanomedicine based on [2]biphenyl-extended-pillar[6]arenes for drug resistance reversal.

A kind of supramolecular polypeptide nanomedicine (BPC/DOX-ICG) was constructed with an anionic water-soluble [2]biphenyl-extended-pillar[6]arene (AWBpP6), and pyridinium-terminal- and S-nitrosothiol (SNO)-modified polypeptide (PPNC) via host-guest interactions to co-deliver doxorubicin (DOX) and indocyanine green (ICG) for drug resistance reversal. Upon near-infrared (NIR) irradiation, the NO generation could down-regulate the P-glycoprotein (P-gp) expression level to reverse multidrug resistance (MDR). Subsequently, the resulting reverse MDR could sensitize the free DOX and assist photothermal therapy (PTT) to enhance the tumoricidal potential. This supramolecular polypeptide nanomedicine provides an effective strategy for the multimodal synergistic therapies of photothermal therapy, NO generation therapy, and chemotherapy (i.e., PTT-NO-CT) to overcome MDR.

Tumor microenvironment responsive polypeptide-based supramolecular nanoprodrugs for combination therapy.

Tumor microenvironment responsive nanomedicine has drawn considerable attention for combination therapy, but still remains a significant challenge for less side effects and enhanced anti-tumor efficiency. Herein, we develop a pH/ROS dual-responsive supramolecular polypeptide nanoprodrug (PFW-DOX/GOD) by using pillar[5]arene-based host-guest strategy for combined glucose degradation, chemodynamic therapy (CDT), and chemotherapy (CT). The PFW-DOX/GOD consists of a pH-responsive ferrocene/pillar[5]arene-containing polypeptide, a ROS-responsive polyprodrug, and encapsulated glucose oxidase (GOD). Upon into intracellular acidic environment, PFW-DOX/GOD exhibits rapid pH-triggered disassembly behavior. Simultaneously, the released GOD can catalyze intratumoral glucose into massive H2O2, which are further converted into highly toxic hydroxyl radicals (•OH) by the catalysis of ferrocene via the Fenton reaction. Thereafter, induced by the ROS-responsive cleavage of thioketal linkage, the conjugated DOX prodrug was released and activated. The combined glucose degradation, chemodynamic therapy (CDT), and chemotherapy (CT) of PFW-DOX/GOD present anti-tumor effect with 96% of tumor inhibitory rate (TIR). Therefore, such tumor microenvironment-responsive supramolecular polypeptide nanoprodrugs represent a potential candidate for combination therapy with minimal side effects. STATEMENT OF SIGNIFICANCE: In this work, a tumor microenvironment-responsive supramolecular polypeptide nanoprodrug (PFW-DOX/GOD) was prepared via pillar[5]arene-based host-guest interactions, and presented low side effects and high tumor accumulation owing to the diameters of about 200 nm and surface PEG segment. After pH-responsive release of GOD in the intracellular acidic environment, the cascade catalytic reactions including GOD-catalyzed degradation of intratumoral glucose and Fenton reaction, effectively happened to generate •OH for chemodynamic therapy (CDT), which subsequently induced the cleavage of thioketal linkage to activate free DOX for chemotherapy (CT). Collectively, this supramolecular polypeptide nanoprodrugs provide a promising strategy for combination therapy with synergetic anti-tumor effect.

pH/ROS dual-responsive supramolecular polypeptide prodrug nanomedicine based on host-guest recognition for cancer therapy.

Supramolecular nanomedicine assembly combined with polypeptide prodrug could become a powerful strategy to minimize drug leakage in blood circulation and trigger sufficient drug release at tumor tissue. Here, we developed a charge-reversal amphiphilic pillar[5]arene-modified polypeptide (P5-PLL-DMA), and reactive oxygen species (ROS)-sensitive polypeptide prodrug (P-PLL-DOX) including a ROS-cleavable thioketal (TK) linker between doxorubicin (DOX) and poly(L-lysine) (PLL), which could assemble via pillar[5]arene host-guest recognition, and further encapsulate chlorin e6 (Ce6) to obtain a supramolecular polypeptide prodrug (SPP-DOX/Ce6). The chemical conjugation to load drugs of DOX and the negatively charge of SPP-DOX/Ce6 could prevent premature drug leakage, and reduce undesirable interaction with serum proteins to enhance stability under physiological conditions (pH 7.4). Simultaneously, the carried charge of SPP-DOX/Ce6 reversed from negative to positive could effectively enhance the cellular internalization for efficient DOX delivery under acidic tumor microenvironment (pH 6.5). Upon 660 nm near-infrared light (NIR) irradiation, the ROS generated by encapsulated Ce6 rapidly cleaved the TK linker to release activated DOX, inducing the tumor-specific drug delivery. This intelligent supramolecular polypeptide prodrug based on pillar[5]arene host-guest recognition represents new avenues to develop stimulus responsive prodrug for enhanced cancer therapy with minimized the side effect. STATEMENT OF SIGNIFICANCE: In this work, a pH/ROS dual-sensitive supramolecular polypeptide prodrug (SPP-DOX/Ce6) was developed to minimize drug leakage in blood circulation and trigger sufficient drug release at tumor tissue. The chemical conjugation to load drugs of DOX via a ROS-cleavable thioketal (TK) linker and the distinctive charge-reversal capacity of SPP-DOX/Ce6 significantly enhances the stability under physiological conditions (pH 7.4), while facilitates cellular uptake at tumor site (pH 6.8). Upon 660 nm near-infrared light (NIR) irradiation, the ROS generated by encapsulated Ce6 induces the rapid cleavage of TK linker to release activated DOX, achieving a tumor-specific drug delivery. This intelligent supramolecular polypeptide prodrug SPP-DOX/Ce6 provides an effective strategy to construct stimulus responsive prodrug for enhanced cancer therapy.

Polydopamine-drug conjugate nanocomposites based on ZIF-8 for targeted cancer photothermal-chemotherapy.

Stimuli-responsive prodrug-based nanoplatform with synergistic antitumor activity is of central importance to the development of promising nanomedicines for cancer therapy. Here, we describe a polydopamine-drug conjugate nanocomposite (ZP-PDA-DOX) with targeted cancer photothermal-chemotherapy (PTT-CT), which constructed by a gradual copolymerization of dopamine (DA) and pH-sensitive dopamine-derived prodrug (DA-DOX) into the porous channels of zeolite imidazolate frameworks-8 (ZIF-8), followed by PEGylation with amino-terminated folic acid-polyethylene glycol (NH2 -PEG-FA) to acquire the high biocompatibility, specificity, and excellent tumor-targeting property. The incorporation of polydopamine strengthened the stability and dispersion of ZIF-8, and also conferred photothermal conversion effect. In the tumor acidic microenvironment, the acid-labile hydrazone linker of DA-DOX and ZIF-8 promptly degraded to release activated DOX. Moreover, the generated hyperthermia due to the high photothermal conversion efficiency of PDA component could accelerate drug release, and simultaneously thermally ablate tumor tissue to maximize the DOX-induced CT, which could also assist PTT to eradicate tumor cells. This study provides a promising strategy for targeted cancer PTT-CT with synergistic anti-tumor effect.