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.

Ding Y ，Wang C ，Ma Y ，Zhu L ，Lu B ，Wang Y ，Wang J ，Chen T ，Dong CM ，Yao Y ... -  《-》

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.

Ding Y ，Wang C ，Ma Y ，Zhu L ，Lu B ，Wang Y ，Wang J ，Dong CM ，Yao Y ... -  《-》

ROS-sensitive thioketal-linked polyphosphoester-doxorubicin conjugate for precise phototriggered locoregional chemotherapy.

Minimizing drug leakage at off-target sites and triggering sufficient drug release in tumor tissue are major objectives for effective nanoparticle (NP)-based cancer therapy. The current covalent and cleavable drug-NP conjugation strategy is promising but lacks high controllability to realize tumor-specific release. As a proof-of-concept, the reactive oxygen species (ROS)-activatable thioketal (TK) bond was explored as the linkage between doxorubicin (DOX) and polyphosphoester (PPE-TK-DOX). The Ce6@PPE-TK-DOX NPs constructed by co-self-coassembly of PPE-TK-DOX and the photosensitizer Ce6 efficiently prevented premature drug leakage in the off-target tissue and cells because of the high stability of the TK bond under physiological conditions. Once circulating into the tumor site, the 660-nm red light was precisely employed to irradiate the tumor area under the guidance of fluorescence/magnetic resonance (MR) dual-model imaging, which can induce localized ROS generation, resulting in rapid cleavage of the TK bond. Consequently, the DOX prodrug was locoregionally released and activated, achieving tumor-specific drug delivery with high controllability by light. Such phototriggered prodrug release and activation at the desired site significantly enhanced the therapeutic efficacy and minimized the side effect, providing new avenues to develop drug delivery systems for remote on-demand drug delivery in vivo.

Pei P ，Sun C ，Tao W ，Li J ，Yang X ，Wang J ... -  《-》

A nanomedicine composed of polymer-ss-DOX and polymer-Ce6 prodrugs with monoclonal antibody targeting effect for anti-tumor chemo-photodynamic synergetic therapy.

Anticancer drugs used for systemic chemotherapy often exhibit off-target toxicity and uncontrolled drug release due to their lack of targeting. To improve the bioavailability of drugs and reduce side effects, we have developed a mixed micelle of nanomedicine composed of two prodrugs with surface modified monoclonal antibody for cancer therapy. In this system, Nimotuzumab was used as targeting ligands of the mixed micelles (named as DCMMs) that is composed of polymer-doxorubicin prodrug (abbreviated as PEG-b-P(GMA-ss-DOX)) and maleimide polyethylene glycol-chlorin e6 (abbreviated as Mal-PEG-Ce6). The mixed micelles modified with Nimotuzumab (named as NTZ-DCMMs) bind to overexpressed EGFR receptors on Hepatoma-22 (H22) cells. Disulfide bonds in PEG-b-P(GMA-ss-DOX) are disrupted in tumor microenvironment, inducing the reduction-responsive release of DOX and leading to tumor cell apoptosis. Simultaneously, Chlorin e6 (Ce6) produced plenty of singlet oxygen (1O2) under laser irradiation to kill tumor cells. In vivo biological distribution and antineoplastic effect experiments demonstrate that NTZ-DCMMs enhanced drug enrichment at tumor sites through targeting function of antibody, dramatically suppressing tumor growth and mitigating cardiotoxicity of drugs. All results prove that NTZ-DCMMs have the ability to actively target H22 cells and quickly respond to tumor microenvironment, which is expected to become an intelligent and multifunctional drug delivery carrier for efficient chemotherapy and photodynamic therapy of hepatoma. STATEMENT OF SIGNIFICANCE: Anticancer drugs used for systemic chemotherapy often exhibit off-target toxicity due to their lack of targeting. Therefore, it's necessary to develop effective, targeted, and collaborative treatment strategies. We construct a mixed micelle of nanomedicine based on two polymer prodrugs and modified with monoclonal antibody on surface for cancer therapy. Under the tumor cell microenvironment, the disulfide bonds of polymer-ss-DOX were broken, effectively triggering DOX release. The photosensitizer Ce6 could generate a large amount of ROS under light, which synergistically promotes tumor cell apoptosis. By coupling antibodies to the hydrophilic segments of polymer micelles, drugs can be specifically delivered. Compared with monotherapy, the combination of chemotherapy and photodynamic therapy can significantly enhance the therapeutic effect of liver cancer.

Yu L ，Zhang M ，He J ，Sun X ，Ni P ... -  《-》

Stimuli-Sensitive Linear-Dendritic Block Copolymer-Drug Prodrug as a Nanoplatform for Tumor Combination Therapy.

Linear-dendritic block copolymer (LDBCs) are highly attractive candidates for smart drug-delivery vehicles. Herein, an amphiphilic poly[(ethylene glycol) methyl ether methacrylate] (POEGMA) linear-peptide dendritic prodrug of doxorubicin (DOX) prepared by reversible addition-fragmentation chain transfer (RAFT) polymerization is reported. The hydrophobic-dye-based photosensitizer chlorin e6 (Ce6) is employed for encapsulation in the prodrug nanoparticles (NPs) to obtain an LDBCs-based drug-delivery system (LD-DOX/Ce6) that offers a combination cancer therapy. Due to the presence of Gly-Phe-Leu-Gly peptides and hydrazone bonds in the prodrug structure, LD-DOX/Ce6 is degraded into small fragments, thus specifically triggering the intracellular release of DOX and Ce6 in the tumor microenvironment. Bioinformatics analysis suggests that LD-DOX/Ce6 with laser irradiation treatment significantly induces apoptosis, DNA damage, and cell cycle arrest. The combination treatment can not only suppress tumor growth, but also significantly reduce tumor metastasis compared with treatments with DOX or Ce6 through regulating EMT pathway, TGFβ pathway, angiogenesis, and the hypoxia pathway. LD-DOX/Ce6 displays a synergistic chemo-photodynamic antitumor efficacy, resulting in a high inhibition in tumor growth and metastasis, while maintaining an excellent biosafety. Therefore, this study demonstrates the potential of the biodegradable and tumor-microenvironment-responsive LDBCs as an intelligent multifunctional drug-delivery vehicle for high-efficiency cancer combination therapy.

Cai H ，Tan P ，Chen X ，Kopytynski M ，Pan D ，Zheng X ，Gu L ，Gong Q ，Tian X ，Gu Z ，Zhang H ，Chen R ，Luo K ... -  《-》