Biomimetic and Wound Microenvironment-Modulating PEGylated Glycopolypeptide Hydrogels for Arterial Massive Hemorrhage and Wound Prohealing.

Despite great progress in the hydrogel hemostats and dressings, they generally lack resistant vascular bursting pressure and intrinsic bioactivity to meet arterial massive hemorrhage and proheal wounds. To address the problems, we design a kind of biomimetic and wound microenvironment-modulating PEGylated glycopolypeptide hydrogels that can be easily injected and gelled in ∼10 s. Those glycopolypeptide hydrogels have suitable tissue adhesion of ∼20 kPa, high resistant bursting pressure of ∼150 mmHg, large microporosity of ∼15 µm, and excellent biocompatibility with ∼1% hemolysis ratio and negligible inflammation. They performed better hemostasis in rat liver and rat and rabbit femoral artery bleeding models than Fibrin glue, Gauze, and other hydrogels, achieving fast arterial hemostasis of <20 s and lower blood loss of 5-13%. As confirmed by in vivo wound healing, immunofluorescent imaging, and immunohistochemical and histological analyses, the mannose-modified hydrogels could highly boost the polarization of anti-inflammatory M2 phenotype and downregulate pro-inflammatory tumor necrosis factor-α to relieve inflammation, achieving complete full-thickness healing with thick dermis, dense hair follicles, and 90% collagen deposition. Importantly, this study provides a versatile strategy to construct biomimetic glycopolypeptide hydrogels that can not only resist vascular bursting pressure for arterial massive hemorrhage but also modulate inflammatory microenvironment for wound prohealing.

Multivalent Polypeptide and Tannic Acid Cooperatively Iron-Coordinated Nanohybrids for Synergistic Cancer Photothermal Ferroptosis Therapy.

Owing to having a unique mechanism to kill cancer cells via the membrane accumulation of lipid peroxide (LPO) and the downregulation of glutathione peroxidase-4 (GPX-4), the ferroptosis therapy (FT) of tumors based on the Fenton reaction of iron nanoparticles has been receiving much attention in the past decade; however, there are some hurdles including the uncontrollable release of iron ions, slower kinetics of the intracellular Fenton reaction, and poor efficacy of FT that need to be overcome. Considering cooperative coordination of a multivalent thiol-pendant polypeptide ligand with iron ions, we put forward a facile strategy for constructing the iron-coordinated nanohybrid of methacryloyloxyethyl phosphorylcholine-grafted polycysteine/iron ions/tannic acid (i.e., PCFT), which could deliver a higher concentration of iron ions into cells. The dynamic and unsaturated coordination in PCFT is favorable for the intracellular stimuli-triggered release and fast Fenton reaction to realize efficient FT, while its intrinsic photothermia would boost the Fenton reaction to induce a synergistic effect between FT and photothermal therapy (PTT). Both immunofluorescence analyses of reactive oxygen species (ROS) and LPO confirmed that the intracellular Fenton reaction resulted in efficient FT, during which process the photothermia greatly boosted ferroptosis, and the Western blot assay corroborated that the expression level of GPX-4 was downregulated by FT and highly degraded by the photothermia to induce synergistic PTT-FT in vitro. Excitingly, by a single intravenous dose of PCFT plus one NIR irradiation, in vivo PTT-FT treatment completely eradicated 4T1 tumors without skin scar and tumor recurrence for 16 days, demonstrating prominent antitumor efficacy, as evidenced by the GPX-4, H&E, and TUNEL assays.

Photoresponsive Polypeptide-Glycosylated Dendron Amphiphiles: UV-Triggered Polymersomes, OVA Release, and In Vitro Enhanced Uptake and Immune Response.

Efficient therapeuic proteins' delivery into mammalian cells and subcellular transport (e.g., fast escape from endolysosomes into cytoplasm) are two key biological barriers that need to be overcome for antigen-based immunotherapy and related biomedical applications. For those purposes, we designed a novel kind of photoresponsive polypeptide-glycosylated poly(amidoamine) (PAMAM) dendron amphiphiles (PGDAs), and their synthesis, UV-responsive self-assembly, and triggered ovalbumin (OVA) release have been fully investigated. The highly anisotropic PGDA4 with a glycosylated second-generation PAMAM dendron self-assembled into stable polypeptide vesicles (polymersomes) within 20-50 wt % water, which exhibited UV-responsive reassembly, dynamic binding with a lectin of concanavalin A, and an accelerated OVA release in vitro. Moreover, upon 365 nm UV irradiation, the self-assembled polymersomes of those glycopolypeptides were transformed into micellar aggregates in aqueous solution at pH 7.4 but disassembled completely at pH 5. The OVA-loaded polymersomes could efficiently deliver OVA into RAW264.7 cells and achieve enhanced endolysosomes escape upon UV irradiation, as revealed by flow cytometry and confocal laser scanning microscopy (CLSM). Furthermore, the enzyme-linked immunosorbent assay (ELISA) showed that the blank sugar-coated polypeptidosomes activated a high level of tumor necrosis factor α (TNF-α) of 468 pg/mL, playing a better role of immune adjuvant for activating the macrophages. Upon the UV irradiation with a dose of 3 J/cm2, the OVA-loaded polymersomes could further stimulate RAW264.7 and enhance the TNF-α level by about 45%. Consequently, this work provides a versatile platform to construct photosensitive and sugar-coated polymersomes of glycopolypeptides that have potential applications for protein delivery, immune adjuvant, and antigen-based immunotherapy.

NIR-Responsive Polypeptide Nanocomposite Generates NO Gas, Mild Photothermia, and Chemotherapy to Reverse Multidrug-Resistant Cancer.

Multidrug resistance (MDR) of cancers that results from overexpression of a P-glycoprotein (P-gp) transporter mainly causes chemotherapy (CT) failure and hinders clinical transitions of current polypeptide nanomedicines. Herein, a novel polypeptide nanocomposite PNOC-PDA that integrates heat-sensitive NO gas delivery and photothermal conversion attributes can overcome MDR and maximize CT; meanwhile the optimized CT and intracellular high-concentration NO gas can assist a mild photothermal therapy (PTT) to eradicate cancer cells. The triple therapies produced a superior and synergistic effect on MDR-reversal and killing MCF-7/ADR in vitro, and the P-gp expression level was downregulated to 46%, as confirmed by means of MTT, Western blot, flow cytometry, and confocal laser scanning microscopy. Significantly, by using one intravenous injection of PNOC-PDA/DOX and a single near-infrared irradiation, the triple therapies of mild PTT, NO gas therapy, and CT achieved complete MCF-7/ADR tumor ablation without skin damage, scarring, and tumor recurrence within 30 days. This work provides a versatile method for the fabrication of NIR-responsive polypeptide nanocomposite with intrinsic photothermal conversion and NO-releasing attributes, opening up a new avenue for reversing MDR in tumors.

Plasmonic, Targeted, and Dual Drugs-Loaded Polypeptide Composite Nanoparticles for Synergistic Cocktail Chemotherapy with Photothermal Therapy.

To integrate cocktail chemotherapy with photothermal therapy into one biocompatible and biodegradable nanocarrier, the plasmonic, lactose-targeted, and dual anticancer drugs-loaded polypeptide composite nanoparticles were for the first time fabricated under mild conditions. The glyco-PEGylated polypeptide micelles that self-assembled from the lactose (LAC) and PEG grafted polycysteine terpolymer were used as templates to generate the plasmonic composite nanoparticles, as mainly characterized by DLS, TEM, SEM, and XPS. These composite nanoparticles showed a broad and strong near-infrared (NIR) absorption at 650-1100 nm and increased the temperature of phosphate buffer solution by 30.1 °C upon a continuous-wave laser irradiation (808 nm, 5 min, 2 W·cm(-2)), while the same dose of NIR-mediated heating completely killed HepG2 cancer cells in vitro, presenting excellent photothermal properties. Two anticancer drugs, doxorubicin (DOX) and 6-mercaptopurine (6-MP), were loaded into the composite nanoparticles through physical interactions and Au-S bond, respectively. The dual drugs-loaded composite nanoparticles exhibited reduction-sensitive and NIR-triggered cocktail drugs release profiles and trigger-enhanced cytotoxicity. As evidenced by flow cytometry, fluorescence microscopy, and MTT assay, the LAC-coated composite nanoparticles were more internalized by the HepG2 than the HeLa cell line, demonstrating a LAC-targeting enhanced cytotoxicity toward HepG2. The combination cocktail chemo-photothermal therapy produced a lower half maximal inhibitory concentration than cocktail chemotherapy or photothermal therapy alone, displaying a good synergistic antitumor effect.

A sweet polydopamine nanoplatform for synergistic combination of targeted chemo-photothermal therapy.

Inspired by sweet or sugar-coated bullets that are used for medications in clinics and the structure and function of biological melanin, a novel kind of sweet polydopamine nanoparticles and their anticancer drug doxorubicin loaded counterparts are prepared, which integrate an active targeting function, photothermal therapy, and chemotherapy into one polymeric nanocarrier. The oxidative polymerization of lactosylated dopamine and/or with dopamine are performed under mild conditions and the resulting sweet nanoparticles are thoroughly characterized. When exposed to an 808 nm continuous-wave diode laser, the magnitude of temperature elevation not only increases with the concentration of nanoparticles, but can also be tuned by the laser power density. The nanoparticles possess strong near infrared light absorption, high photothermal conversion efficiency, and good photostability. The nanoparticles present tunable binding with RCA120 lectin and a targeting effect to HepG2 cells, confirmed by dynamic light scattering, turbidity analysis, MTT assay, and flow cytometry. Importantly, the sweet nanoparticles give the lowest IC50 value of 11.67 µg mL(-1) for chemo-photothermal therapy compared with 43.19 µg mL(-1) for single chemotherapy and 67.38 µg mL(-1) for photothermal therapy alone, demonstrating a good synergistic effect for the combination therapy.

Multi-responsive polypeptidosome: characterization, morphology transformation, and triggered drug delivery.

The biodegradable polymeric nanomedicines that may be integrated with multi-stimuli-sensitivity to achieve triggered or on-demand drug release kinetics are challenging for polymer therapeutics and drug delivery systems. By controlling the structure transformation of one polypeptide-b-PEO copolymer, a novel multi-responsive polypeptide-based vesicle (polypeptidosome) presents the combined sensitivity of multiple physiological and clinic-related stimuli, and both morphology and size of the polypeptidosome are changed during the triggered process. The designer polypeptide has unique structures composed of 1) light-responsive o-nitrobenzyl groups, 2) oxidizable thioether linkers, 3) photo-caged redox thiol groups on parent poly(L-cysteine), and 4) tunable conformation, which enable the polypeptidosome to have a peculiar multi-response. The anticancer drug doxorubicin can be released in a controlled or on-off manner. The combination stimuli of UV irradiation and H2 O2 oxidation induces a large effect and a lower IC50 of 3.80 µg doxorubicin (DOX) equiv/mL compared to 5.28 µg DOX equiv/mL of individual H2 O2 trigger.

All-in-one polysaccharide hydrogel with resistant vascular burst pressure and cooperative wound microenvironment regulation for fatal arterial hemorrhage and diabetic wound healing.

Fatal massive hemorrhage and diabetic wound healing are world widely challenging in surgical managements, and uncontrolled bleeding, chronic inflammation and damaged remodeling heavily hinder the whole healing processes. Considering hemostasis, inflammation and wound microenvironment cooperatively affect the healing progression, we design all-in-one beta-glucan (BG) hybrid hydrogels reinforced with laponite nanoclay that demonstrate tunable tissue adhesion, resistant vascular burst pressure and cooperative wound microenvironment regulation for arterial hemostasis and diabetic wound prohealing. Those hydrogels had honeycomb-like porous microstructure with average pore size of 7-19 µm, tissue adhesion strength of 18-46 kPa, and vascular burst pressure of 58-174 mmHg to achieve superior hemostasis in rat liver and femoral artery models. They could effectively scavenge reactive oxygen species, transform macrophages from proinflammatory M1 into prohealing M2, and shorten the inflammation duration via synergistic actions of BG and nitric oxide (NO). Single treatment of NO-releasing BG hybrid hydrogels attained complete closure of diabetic wounds within 14 days, orchestrated to accelerate the epithelization and dermis growth, and restored normal vascularization, achieving high performance healing with optimal collagen deposition and hair follicle regeneration. Consequently, this work opens up a new avenue to design all-in-one polysaccharide hydrogels for applications in massive bleeding hemostats and diabetic wound dressings.

Wound microenvironment regulatory poly(L-glutamic acid) composite hydrogels containing metal ion-coordinated nanoparticles for effective hemostasis and wound healing.

Regulating the wound microenvironment to promote proliferation, vascularization, and wound healing is challenging for hemostats and wound dressings. Herein, polypeptide composite hydrogels have been simply fabricated by mixing a smaller amount of metal ion-coordinated nanoparticles into dopamine-modified poly(L-glutamic acid) (PGA), which had a microporous size of 10-16 µm, photothermal conversion ability, good biocompatibility, and multiple biological activities. In vitro scratch healing of fibroblast L929 cells and the tube formation of HUVECs provide evidence that the PGA composite hydrogels could promote cell proliferation, migration, and angiogenesis with the assistance of mild photothermia. Moreover, these composite hydrogels plus mild photothermia could effectively eliminate reactive oxygen species (ROS), alleviate inflammation, and polarize the pro-inflammatory M1 macrophage phenotype into the pro-healing M2 phenotype to accelerate wound healing, as assessed by means of fluorescent microscopy, flow cytometry, and quantitative real-time polymerase chain reaction (qRT-PCR). Meanwhile, a rat liver bleeding model illustrates that the composite hydrogels reduced the blood loss ratio to about 10% and shortened the hemostasis time to about 25 s better than commercial chitosan-based hemostats. Furthermore, the full-thickness rat skin defect models showcase that the composite hydrogels plus mild photothermia could proheal wounds completely with a fast healing rate, optimal neovascularization, and collagen deposition. Therefore, the biodegradable polypeptide PGA composite hydrogels are promising as potent wound hemostats and dressings.

Synthesis of hyperbranched polypeptide and PEO block copolymer by consecutive thiol-yne chemistry.

Hyperbranched poly(ε-benzyloxycarbonyl-L-lysine) (HPlys) with multiple alkyne peripheries was synthesized through the click polycondensation of an AB2 type Plys macromonomer with α-thiol and ω-alkyne terminal groups (thiol is the A unit, and each π bond in alkyne is the B unit), and the resulting HPlys was further conjugated with thiol-termined poly(ethylene oxide) (PEO) to generate HPlys-b-PEO block copolymer by consecutive thiol-yne chemistry. Their molecular structures and physical properties were characterized in detail by FT-IR, (1)H NMR, gel permeation chromatography, differential scanning calorimetry, wide-angle X-ray diffraction, and polarized optical microscopy. HPlys and HPlys-b-PEO mainly assumed an α-helix conformation similar to the linear precursors, while the liquid crystalline phase transition of Plys segment disappeared within HPlys and HPlys-b-PEO. HPlys-b-PEO self-assembled into nearly spherical micelles in aqueous solution, while it gave a 5-fold lower critical aggregation concentration (8.9 × 10(-3) mg/mL) than a linear counterpart (4.5 × 10(-2) mg/mL), demonstrating a dendritic topology effect. Compared with a linear counterpart, HPlys-b-PEO gave a higher drug-loading capacity and efficiency for the anticancer drug doxorubicin (DOX) and a slower drug-release rate with an improved burst-release profile, enabling them useful for drug delivery systems. Importantly, this work provides a versatile strategy for the synthesis of hyperbranched polypeptides and related block copolymers by utilizing thiol-yne chemistry.

Biocompatible Polymer-Modified Nanoplatform for Ferroptosis-Enhanced Combination Cancer Therapy.

Ferroptosis is a novel type of iron-dependent non-apoptotic pathway that regulates cell death and shows unique mechanisms including causing lipid peroxide accumulation, sensitizing drug-resistant cancers, priming immunity by immunogenic cell death, and cooperatively acting with other anticancer modalities for eradicating aggressive malignancies and tumor relapse. Recently, there has been a great deal of effort to design and develop anticancer biocompatible polymeric nanoplatforms including polypeptide and PEGylated ones to achieve effective ferroptosis therapy (FT) and synergistic combination therapies including chemotherapy (CT), photodynamic therapy (PDT), sonodynamic therapy (SDT), photothermal therapy (PTT), gas therapy (GT) including nitric oxide (NO), carbon monoxide (CO), and hydrogen sulfide (H2 S), and immunotherapy (IT). To be noted, the combo therapies such as FT-CT, FT-PTT, FT-GT, and FT-IT are attracting much efforts to fight against intractable and metastatic tumors as they can generate synergistic antitumor effects and immunogenic cell death (ICD) effects or modulate immunosuppressive tumor microenvironments to initiate strong antitumor immunity and memory effects. The polymeric Fenton nano-agents with good biosafety and high anticancer efficacy will provide a guarantee for their applications. In this review, various biocompatible polymer-modified nanoplatforms designed for FT and combo treatments are summarized for anticancer therapies and discussed for potential clinical transitions.

Photoresponsive poly(S-(o-nitrobenzyl)-L-cysteine)-b-PEO from a L-cysteine N-carboxyanhydride monomer: synthesis, self-assembly, and phototriggered drug release.

A photoresponsive S-(o-nitrobenzyl)-l-cysteine N-carboxyanhydride (NBC-NCA) monomer was for the first time designed, and the related poly(S-(o-nitrobenzyl)-l-cysteine)-b-poly(ethylene glycol) (PNBC-b-PEO) block copolymers were synthesized from the ring-opening polymerization (ROP) of NBC-NCA in DMF solution at 25 °C. Their molecular structures, physical properties, photoresponsive self-assembly, and drug release of PNBC-b-PEO were thoroughly investigated. The ß-sheet conformational PNBC block within copolymers presented a thermotropic liquid crystal phase behavior, and the crystallinity of PEO block was progressively suppressed over the PNBC composition. The characteristic absorption peaks of these copolymers at about 310 and 350 nm increased over UV irradiation time and then leveled off, indicating that the o-nitrobenzyl groups were gradually photocleaved from copolymers until the completion of photocleavage. The PNBC-b-PEO copolymers self-assembled into spherical nanoparticles in aqueous solution, presenting a photoresponsive self-assembly behavior, together with a size reduction of nanoparticles after irradiation. The anticancer drug doxorubicin can be released in a controlled manner by changing the light irradiation time, which was induced by gradually photocleaving the PNBC core of nanoparticles. This work provides a facile strategy not only for the synthesis of photoresponsive polypeptide-based block copolymers but also for the fabrication of photoresponsive nanomedicine potential for anticancer therapy.

NIR-responsive and lectin-binding doxorubicin-loaded nanomedicine from Janus-type dendritic PAMAM amphiphiles.

Janus-type dendritic poly(amido amine) (PAMAM) amphiphiles Dm-Lac-D3DNQ were synthesized by connecting hydrophobic diazonaphthoquinone (DNQ)-decorated PAMAM dendron D3 (generation 3) and hydrophilic lactose (Lac)-decorated PAMAM dendrons Dm (generations 0-2, m = 0-2) via click chemistry. They self-assembled into the DNQ-cored micelles dangled by densely free Lac groups in aqueous solution. Irradiated by 808 nm laser and 365 nm lamp, both NIR- and UV-sensitivity of micelles were characterized by time-resolved UV-vis spectroscopy. The characteristic absorption intensity of DNQ progressively decreased and then leveled off. Moreover, the bigger the micelles, the more the irradiation time for finishing Wolff rearrangement of DNQ. TEM further confirmed that most of the micelles disassembled after 30 min of 808 nm laser irradiation. The Lac-coated micelles showed binding with RCA(120) lectin, as monitored by UV-vis and DLS. The apparent drug-release rate of doxorubicin (DOX) loaded nanomedicine nearly doubled after 10 min of 808 nm laser irradiation, presenting a NIR-triggered drug-release profile. Moreover, the DOX-loaded nanomedicine presented a phototriggered cytotoxicity that was close to free DOX, and they could quickly enter into HeLa cells, as evidenced by MTT assay, flow cytometry, and CLSM. Importantly, this work provides a versatile strategy for the fabrication of NIR-responsive and lectin-binding dendrimer nanomedicine, opening a new avenue for "on-demand" and spatiotemporal drug delivery.

Multifunctional Single-Component Polypeptide Hydrogels: The Gelation Mechanism, Superior Biocompatibility, High Performance Hemostasis, and Scarless Wound Healing.

Polymeric hydrogels have been increasingly studied for wound sealants, adhesives, hemostats, and dressings, however, multi-component gelation, adhesion-causing tissue damage, inefficient hemostasis, and skin scarring in wound healing hamper their advances. So it is urgent to develop multifunctional single-component polymeric hydrogels with benign tissue detachment, high performance hemostasis, and scarless wound healing attributes. Herein, a dopamine-modified poly(l-glutamate) hydrogel at an ultralow concentration of 0.1 wt% is serendipitously constructed by physical treatments, in which a gelation mechanism is disclosed via oxidative catechol-crosslinking and sequential dicatechol-carboxyl hydrogen-bonding interactions. The covalent/H-bonding co-crosslinked and highly negative-charged networks enable the polypeptide hydrogels thermo-, salt-, urea-resistant, self-healing, injectable, and adhesive yet detachable. In vitro and in vivo assays demonstrate they have superior biocompatibility with ≈0.5% hemolysis and negligible inflammation. The polypeptide/graphene oxide hybrid hydrogel performs fast and efficient hemostasis of 12 s and 1.4% blood loss, surpassing some hydrogels and commercial counterparts. Remarkably, the polypeptide hydrogels achieve scarless and full wound healing and regenerate thick dermis with some embedded hair follicles within 14 days, presenting superior full-thickness wound healing and skin scar-preventing capabilities. This work provides a simple and practicable method to construct multifunctional polypeptide hemostatic and healing hydrogels that overcome some above-mentioned hurdles.

Stimuli-responsive polypeptide nanoassemblies: Recent progress and applications in cancer nanomedicine.

Stimuli-responsive polypeptide nanoassemblies exhibit great potentials for cancer nanomedicines because of desirable biocompatibility and biodegradability, unique secondary conformations, varying functionalities, and especially the stimuli-enhanced therapeutic efficacy and reduced side effect. This review introduces the design and fabrication of stimuli-responsive polypeptide nanoassemblies that exhibit endogenous stimuli (e.g., pH, reduction, reactive oxygen species, adenosine triphosphate and enzyme, etc.) and exogenous light stimuli (e.g., UV and near-infrared light), which are biologically related or applied in the clinic. We also discuss the applications and prospects of those stimuli-responsive polypeptide nanoassemblies that might overcome the biological barriers of cancer nanomedicines for in vivo administration. Much more effort is needed to accelerate the second-generation stimuli-responsive polypeptide nanomedicines for clinical transition and applications. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease.

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.

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.

Two-photon-sensitive and sugar-targeted nanocarriers from degradable and dendritic amphiphiles.

Increasing efforts are being put into the light-sensitive polymeric micelles that hold great potential for drug/gene/small interfering RNA delivery. However, these polymeric micelles lack highly efficient tumor-targeting properties and near-infrared light sensitivity, and often exhibit an uncontrollable drug-release profile. To address these problems, a new strategy is introduced that combines sugar-triggered targeting (active targeting) and two-photon sensitivity to afford a degradable and dendritic micellar nanocarrier, in which the desired sugar residues and light-responsive groups can be modularly conjugated and/or altered. A clinical anticancer drug, doxorubicin, can be released in a controlled manner by changing the light irradiation time, which is induced by the gradual disruption of micelles in aqueous solution. The glucose- and lactose-coated micelles further demonstrate specific binding with the lectins Concanavalin A and Ricinus communis agglutinin, respectively, which makes them useful as targeted drug-delivery vesicles.

Polymeric photothermal agents for cancer therapy: recent progress and clinical potential.

Over the past decades, near infrared light (NIR)-sensitive photothermal agents (PTAs) that can efficiently absorb light and generate heat have been investigated worldwide for cancer photothermal therapy (PTT) and the combination treatments, which have some peculiar advantages including spatiotemporal targeting, the ability-to-reverse multidrug resistance, the immunity-stimulating function, and the synergistic effect in combination treatments. In this review, we first focus on emerging melanin-like polymers and coordination polyphenol polymer-based PTAs that hold transition potential because of their facile synthesis and good biocompatibility/biodegradability. We briefly introduce polymeric PTAs for emerging NIR-II (1000-1700 nm) PTT in deep tumors to overcome shallow penetration depth and threshold irradiation intensity of NIR-I (700-900 nm). Then we discuss polymeric PTAs for combination PTT treatments with photodynamic therapy (PDT), ferroptosis therapy (ferrotherapy), and immunotherapy, which are intensively studied for achieving anticancer synergistic effects. Finally, we discuss those polymeric PTAs for reversing cancer multidrug resistance and for mild/low-temperature PTT (43 °C ≤ T < 50 °C) in contrast to conventional high-temperature PTT (>50 °C). The polymeric PTA-based PTT and the combination treatments are still being developed in the early stage and need much more effort before potential clinical transitions and applications.