Notch-targeted Therapeutic in Colorectal Cancer by Notch1 Attenuation via Tumor Microenvironment-Responsive Cascade DNA Delivery.

The Notch signaling is a key molecular pathway that regulates cell fate and development. Aberrant Notch signaling can lead to carcinogenesis and progression of malignant tumors. However, current therapies targeting Notch pathway lack specificity and induce high toxicity. In this report, we design a tumor microenvironment-responsive and injectable hydrogel to load plasmid DNA complexes as a cascade gene delivery system to achieve precise Notch-targeted gene therapy of colorectal cancer (CRC). The hydrogels were prepared through cross-linking between phenylboric acid groups-containing poly(oligo(ethylene glycol)methacrylate) (POEGMA) and epigallocatechin gallate (EGCG), which were used to load the complexes between plasmid DNA encoding short hairpin RNAs of Notch1 (shNotch1) and fluorinated polyamidoamine (PAMAM-F) (PAMAM-F/shNotch1). In response to low pH and H2O2 in tumor microenvironment, the hydrogel can be dissociated and release the complexes for precise delivery of shNotch1 into tumor cells and inhibit Notch1 activity to suppress malignant biological behaviors of CRC. In the subcutaneous tumor model of CRC, PAMAM-F/shNotch1-loaded hydrogels can accurately attenuate Notch1 activity and significantly inhibit tumor growth without affecting Notch signal in adjacent normal tissues. Therefore, this therapeutic system can precisely inhibit Notch1 signal in CRC with high responsiveness and low toxicity, providing a promising Notch-targeted gene therapeutic for human malignancy. This article is protected by copyright. All rights reserved.

Luminescent Perovskite-Cross-Linked Polymer with Low Shrinkage and Excellent Stability.

When organic cross-linked polymers are combined with metal halide perovskite nanocrystals (PNCs) for realizing luminescent perovskite-polymer display materials, the stability of PNCs is enhanced and their shrinkage is suppressed. This work presents a feasible strategy for preparing CsPbBr3 nanocrystals (NCs) within a polydicyclopentadiene (PDCPD) thermosetting cross-linked resin matrix simultaneously via a one-step reaction. The obtained PDCPD@PNCs composite exhibits narrow peak half-widths (15-20 nm), high light transmittance (80%), low curing volume shrinkage (1.4%), tunable tensile properties, excellent stability, and a photoluminescence quantum yield (PLQY) of 44.3%. The composite material exhibits long-term stability in water, acid, and base solutions for over 90 days, with the PL intensity being maintained at over 90%. Furthermore, the composite is highly resistant to polar organic solvents owing to the insolubility imparted by cross-linking. White LEDs (WLED) fabricated using the as-prepared composite demonstrate excellent potential as light sources in optical devices.

Dynamic Thermosetting Resins with Synergistic Enhanced Strength and Toughness through Combination with Rigid and Soft Microdomains.

Preparation of materials that possess highly strong and tough properties simultaneously is a great challenge. Thermosetting resins as a type of widely used polymeric materials without synergistic strength and toughness limit their applications in some special fields. In this report, an effective strategy to prepare thermosetting resins with synergistic strength and toughness, is presented. In this method, the soft and rigid microspheres with dynamic hemiaminal bonds are fabricated first, followed by hot-pressing to crosslink at the interfaces. Specifically, the rigid or soft microspheres are prepared via precipitation polymerization. After hot-pressing, the resulting rigid-soft blending materials exhibit superior strength and toughness, simultaneously. As compared with the precursor rigid or soft materials, the toughness of the rigid-soft blending films (RSBFs) is improved to 240% and 2100%, respectively, while the strength is comparable to the rigid precursor. As compared with the traditional crushing, blending, and hot-pressing of rigid or soft materials to get the nonuniform materials, the strength and toughness of the RSBFs are improved to 168% and 255%, respectively. This approach holds significant promise for the fabrication of polymer thermosets with a unique combination of strength and toughness.

Dynamic Cross-Linked Polyethylene Networks with High Energy Storage and Electrical Damage Self-Healability.

Dielectric polymers that exhibit high energy density Ue, low dielectric loss, and thermal resistance are ideal materials for next-generation electrical equipment. The most widely utilized approach to improving Ue involves augmenting the polarization through increasing the dielectric constant εr or the breakdown strength Eb. However, as a conflicting parameter, the dielectric loss also increases inevitably at the same time. In addition, due to the long-term work under a strong electric field or high potential, dielectric materials often produce electrical damage (electrical tree), which is one of the main factors affecting the reliability and service life of electrical equipment. To address these problems, we herein develop dynamic cross-linked polyethylene materials (PE-MA-Epo) by polyethylene-graft-maleic anhydride (PE-MA) and polar epoxy monomers, which showed high εr (>7), low dielectric loss (<0.02), high Ue (5.16 J/cm3 at 425 MV/m), and outstanding discharge efficiency (97%). The performances of the materials are adequate to rival biaxially oriented polypropylene (BOPP) films. Moreover, the excellent self-healing capability of PE-MA-Epo enables the total recovery of εr and tan δ after electrical tree healing. After two cycles of electrical breakdown healing, Eb remained at 80%, which improves the durability and reliability of dielectric polymers. Therefore, PE-MA-Epo shows great potential for applications in advanced electronic power devices.

Polymersome Membrane Engineering with Active Targeting or Controlled Permeability for Responsive Drug Delivery.

Polymersomes have been extensively investigated for drug delivery as nanocarriers for two decades due to a series of advantages including high stability under physiological conditions, simultaneous encapsulation of hydrophilic and hydrophobic drugs inside inner cavities and membranes, respectively, and facile adjustment of membrane and surface properties, as well as controlled drug release through incorporation of stimuli-responsive components. Despite these features, polymersome nanocarriers frequently suffer from nontargeting delivery and poor membrane permeability. In recent years, polymersomes have been functionalized for more efficient drug delivery. The surface shells were explored to be modified with diverse active targeting groups to improve disease-targeting delivery. The membrane permeability of the polymersomes was adjusted by incorporation of the stimuli-responsive components for smart controlled transportation of the encapsulated drugs. Therefore, being the polymersome-biointerface, tailorable properties can be introduced by its carefully modulated engineering. This review elaborates on the role of polymersome membranes as a platform to incorporate versatile features. First, we discuss how surface functionalization facilitates the directional journey to the targeting sites toward specific diseases, cells, or intracellular organelles via active targeting. Moreover, recent advances in the past decade related to membrane permeability to control drug release are also summarized. We finally discuss future development to promote polymersomes as in vivo drug delivery nanocarriers.

Molecular Clogging Organogels with Excellent Solvent Maintenance, Adjustable Modulus, and Advanced Mechanics for Impact Protection.

Inspired by mechanically interlocking supramolecular materials, exploiting the size difference between the bulky solvent and the cross-linked network mesh, a molecular clogging (MC) effect is developed to effectively inhibit solvent migration in organogels. A bulky solvent (branched citrate ester, BCE) with a molecular size above 1.4 nm is designed and synthesized. Series of MC-Gels are prepared by in situ polymerization of crosslinked polyurea with BCE as the gel solvent. The MC-Gels are colorless, transparent, and highly homogeneous, show significantly improved stability than gels prepared with small molecule solvents. As solvent migration is strongly inhibited by molecular clogging, the solvent content of the gels can be precisely controlled, resulting in a series of MC-Gels with continuously adjustable mechanics. In particular, the modulus of MC-Gel can be regulated from 1.3 GPa to 30 kPa, with a variation of 43 000 times. The molecular clogging effect also provides MC-Gels with unique high damping (maximum damping factor of 1.9), impact resistant mechanics (high impact toughness up to 40.68 MJ m-3 ). By applying shatter protection to items including eggs and ceramic armor plates, the potential of MC-Gels as high strength, high damping soft materials for a wide range of applications is well demonstrated.

X-ray-responsive prodrugs and polymeric nanocarriers for multimodal cancer therapy.

Radiotherapy as one of the most important cancer treatment modalities has been widely used in the therapy of various cancers. The clinically used radiation (e.g. X-ray) for radiotherapy has the advantages of precise spatiotemporal controllability and deep tissue penetration. However, traditional radiotherapy is frequently limited by the high side effects and tumor hypoxia. The combination of radiotherapy and other cancer treatment modalities may overcome the disadvantages of radiotherapy and improve the final therapeutic efficacy. In recent years, X-ray-activable prodrugs and polymeric nanocarriers have been extensively explored to introduce other treatment modalities in the precise position during radiotherapy, which can reduce the side toxicity of the drugs and improve the combination therapeutic efficacy. In this review, we focus on recent advances in X-ray-activable prodrugs and polymeric nanocarriers to boost X-ray-based multimodal synergistic therapy with reduced toxicity. The design strategies of prodrugs and polymeric nanocarriers are highlighted. Finally, challenges and outlooks of X-ray-activable prodrugs and polymeric nanocarriers are discussed.

Hard-Soft Thermoset Alloy with Enhanced Toughness, Impact-Resistance, and Electric Conductivity via Interpenetrated Dynamic Crosslinked Interface.

Polymer alloys (PAs) are mixtures of two or more types of polymers to enhance the properties of polymeric materials. However, thermosets with crosslinked structures are immiscible and cannot be prepared PAs. Herein, two immiscible covalent adaptable networks containing phenoxy carbamate bonds are explored as the typical polymeric materials to prepare the hard-soft thermoset alloy (HSTA) by the interpenetrated dynamic crosslinked interface (IDCI) to enhance the toughness. Specifically, two types of polyurethane covalent adaptable networks with either high stiffness (thermoset) or extensibility (elastomer) are prepared, respectively. The granules of thermoset and elastomer are mixed and hot-pressed to prepare the HSTA. The HSTA shows improved mechanical properties with a toughness of 22.8 MJ m-3 which is 14 times higher than that of hard thermoset. In addition, the HSTA shows excellent impact-resistance property after 1000 punctures. Moreover, the obtained HSTA via addition of carbon nanotubes can significantly decrease the electric resistance over six orders of magnitudes as compared to the blending method, which is due to the distribution of the carbon nanotubes at the interfaces of the two networks.

Oxidation-Responsive PolyMOF Nanoparticles for Combination Photodynamic-Immunotherapy with Enhanced STING Activation.

Stimulator of interferon genes (STING) activation by STING agonists has been recognized as one of the potent and promising immunotherapy strategies. However, the immunosuppressive tumor microenvironment always hinders the therapeutic efficacy of cancer immunotherapy. In this report, we present polymeric metal-organic framework (PMOF) nanoparticles (NPs) for the combination of photodynamic therapy (PDT) and enhanced STING activation to improve the immunotherapeutic efficacy. The PMOF NPs with poly(ethylene glycol) (PEG) shells were obtained via coordination between the block copolymer ligand PEG-b-PABDA consisting of 1,4-bezenedicarboxylic acid-bearing polyacrylamide (PABDA), meso-tetra(carboxyphenyl)porphyrin (TCPP), thioketal diacetic acid, and zirconyl chloride. Subsequently, the STING agonist SR-717 was loaded into the porous structure of PMOF to obtain SR@PMOF NPs which show excellent stability under the physiological conditions. After intravenous injection and tumor accumulation, light irradiation on the tumor sites results in efficient singlet oxygen (1O2) production from TCPP and cellular apoptosis to release fragmented DNA and tumor-associated antigens. Simultaneously, thioketal bonds can be broken by 1O2 to destroy the PMOF structure and rapidly release SR717. SR-717 and PDT synergistically enhance the antitumor immunity via combination photodynamic-immunotherapy due to reversal of the immunosuppressive tumor microenvironment and enhanced endogenous STING activation, which can suppress the growth of the primary and distant tumors efficiently. The oxidation-responsive SR@PMOF NPs represent a promising delivery system of STING agonists and efficient PDT NPs for simultaneous suppression of the primary and metastatic tumors via the rational combination of PDT and enhanced STING activation.

Thioaminal Covalent Adaptable Networks via Thiol-Aldehyde-Amine Multicomponent Polymerization.

Multicomponent polymerization (MCP) has the advantages of high efficiency, mild reaction conditions, and high yield and has been widely used to synthesize multifunctional polymers. In this report, we develop novel covalent adaptable networks (CANs) with dynamic thioaminal covalent bonds via a simple one-pot thiol-aldehyde-amine MCP. The dynamic behaviors of the thioaminal group are demonstrated. The obtained thioaminal CANs show the tensile strength of as high as 45 MPa via MCP of pentaerythritol tetra(3-mercaptopropionate), the mixture of formaldehyde and benzaldehyde, and 4,4'-methylenedianiline. Moreover, the CANs exhibit reprocessability, recyclability, and reconfigurable shape memory behaviors. Thus, the thiol-aldehyde-amine MCP represents a simple and efficient strategy for the preparation of versatile thioaminal CANs.

Highly Tough and Reliable Poly(Amic Acid) with Ballistic Impact-Resistance through Modulation of Hydrogen Bonding Interactions.

Poly(amic acid) (PAA) materials as the precursor of polyimide generally show remarkably poor mechanical properties, thus limiting their application as the engineering plastics. In this study, it is demonstrated that the mechanical properties of PAA materials can be improved significantly for tens of folds with breaking strength >50 MPa, Young's modulus >400 MPa, and elongation at break >300% by incorporation of 20% (mol%) poly(propylene glycol) (PPO) soft segments. The optimization for suitable hard-soft composition with 20% PPO and the existence of various hydrogen bonds with different binding energies can dissipate energies efficiently, which simultaneously improve the material strength and toughness. In addition, PAA82 films exhibit excellent tolerance toward cyclic stretch, and have the capability to resist various harsh conditions including solar radiation testing (1 sun), heat (85 °C), alkalinity (pH 10), and acidity (pH 4) over one month. Noted that PAA82 films can be laminated with Kapton films, which show excellent resistance to ultrahigh (200 °C) and ultralow temperature (-196 °C). The laminated film also exhibits bulletproof property with a thickness of 6 mm. The strategy via modulation of hard-soft compositions and hydrogen bonds in PAA materials shows great potentials to improve the mechanical properties of polymeric materials.

Extremely Strong and Tough Biodegradable Poly(urethane) Elastomers with Unprecedented Crack Tolerance via Hierarchical Hydrogen-Bonding Interactions.

The elastomers with the combination of high strength and high toughness have always been intensively pursued due to their diverse applications. Biomedical applications frequently require elastomers with biodegradability and biocompatibility properties. It remains a great challenge to prepare the biodegradable elastomers with extremely robust mechanical properties for in vivo use. In this report, we present a polyurethane elastomer with unprecedented mechanical properties for the in vivo application as hernia patches, which was obtained by the solvent-free reaction of polycaprolactone (PCL) and isophorone diisocyanate (IPDI) with N,N-bis(2-hydroxyethyl)oxamide (BHO) as the chain extender. Abundant and hierarchical hydrogen-bonding interactions inside the elastomers hinder the crystallization of PCL segments and facilitate the formation of uniformly distributed hard phase microdomains, which miraculously realize the extremely high strength and toughness with the fracture strength of 92.2 MPa and true stress of 1.9 GPa, while maintaining the elongation-at-break of ≈1900% and ultrahigh toughness of 480.2 MJ m-3 with the unprecedented fracture energy of 322.2 kJ m-2 . Hernia patches made from the elastomer via 3D printing technology exhibit outstanding mechanical properties, biocompatibility, and biodegradability. The robust and biodegradable elastomers demonstrate considerable potentials for in vivo applications.

Mitochondria-Targeting Polyprodrugs to Overcome the Drug Resistance of Cancer Cells by Self-Amplified Oxidation-Triggered Drug Release.

The multi-drug resistance (MDR) of cancers is one of the main barriers for the success of diverse chemotherapeutic methods and is responsible for most cancer deaths. Developing efficient approaches to overcome MDR is still highly desirable for efficient chemotherapy of cancers. The delivery of targeted anticancer drugs that can interact with mitochondrial DNA is recognized as an effective strategy to reverse the MDR of cancers due to the relatively weak DNA-repairing capability in the mitochondria. Herein, we report on a polyprodrug that can sequentially target cancer cells and mitochondria using folic acid (FA) and tetraphenylphosphonium (TPP) targeting moieties, respectively. They were conjugated to the terminal groups of the amphiphilic block copolymer prodrugs composed of poly[oligo(ethylene glycol) methyl ether methacrylate] (POEGMA) and copolymerized monomers containing cinnamaldehyde (CNM) and doxorubicin (DOX). After self-assembly into micelles with the suitable size (∼30 nm), which were termed as TF@CNM + DOX, and upon intravenous administration, the micelles can accumulate in tumor tissues. After FA-mediated endocytosis, the endosomal acidity (∼pH 5) can trigger the release of CNM from TF@CNM + DOX micelles, followed by enhanced accumulation into the mitochondria via the TPP target. This promotes the overproduction of reactive oxygen species (ROS), which can subsequently enhance the intracellular oxidative stress and trigger ROS-responsive release of DOX into the mitochondria. TF@CNM + DOX shows great potential to inhibit the growth of DOX-resistant MCF-7 ADR tumors without observable side effects. Therefore, the tumor and mitochondria dual-targeting polyprodrug design represents an ideal strategy to treat MDR tumors through improvement of the intracellular oxidative level and ROS-responsive drug release.

Multifunctional Mesoporous Hollow Cobalt Sulfide Nanoreactors for Synergistic Chemodynamic/Photodynamic/Photothermal Therapy with Enhanced Efficacy.

The unique tumor microenvironment (TME) characteristic of severe hypoxia, overexpressed intracellular glutathione (GSH), and elevated hydrogen peroxide (H2O2) concentration limit the anticancer effect by monotherapy. In this report, glucose oxidase (GOx)-encapsulated mesoporous hollow Co9S8 nanoreactors are constructed with the coverage of polyphenol diblock polymers containing poly(oligo(ethylene glycol) methacrylate) and dopamine moieties containing methacrylate polymeric block, which are termed as GOx@PCoS. After intravenous injection, tumor accumulation, and cellular uptake, GOx@PCoS deplete GSH by Co3+ ions. GOx inside the nanoreactors produce H2O2 via oxidation of glucose to enhance •OH-based chemodynamic therapy (CDT) through the Fenton-like reaction under the catalysis of Co2+. Moreover, Co3+ ions possess catalase activity to catalyze production of O2 from H2O2 to relieve tumor hypoxia. Upon 808 nm laser irradiation, GOx@PCoS exhibit photothermal and photodynamic effects with a high photothermal conversion efficiency (45.06%) and generation capacity of the toxic superoxide anion (•O2-) for photothermal therapy (PTT) and photodynamic therapy (PDT). The synergetic antitumor effects can be realized by GSH depletion, starvation, and combined CDT, PTT, and PDT with enhanced efficacy. Notably, GOx@PCoS can also be used as a magnetic resonance imaging (MRI) contrast agent to monitor the antitumor performance. Thus, GOx@PCoS show great potentials to effectively modulate TME and perform synergistic multimodal therapy.

Protein-Delivering Nanocomplexes with Fenton Reaction-Triggered Cargo Release to Boost Cancer Immunotherapy.

Immunotherapeutic efficacy of tumors based on immune checkpoint blockade (ICB) therapy is frequently limited by an immunosuppressive tumor microenvironment and cross-reactivity with normal tissues. Herein, we develop reactive oxygen species (ROS)-responsive nanocomplexes with the function of ROS production for delivery and triggered release of anti-mouse programmed death ligand 1 antibody (αPDL1) and glucose oxidase (GOx). GOx and αPDL1 were complexed with oligomerized (-)-epigallocatechin-3-O-gallate (OEGCG), which was followed by chelation with Fe3+ and coverage of the ROS-responsive block copolymer, POEGMA-b-PTKDOPA, consisting of poly(oligo(ethylene glycol)methacrylate) (POEGMA) and the block with thioketal bond-linked dopamine moieties (PTKDOPA) as the side chains. After intravenous injection, the nanocomplexes show prolonged circulation in the bloodstream with a half-life of 8.72 h and efficient tumor accumulation. At the tumor sites, GOx inside the nanocomplexes can produce H2O2 via oxidation of glucose for Fenton reaction to generate hydroxyl radicals (•OH) which further trigger the release of the protein cargos through ROS-responsive cleavage of thioketal bonds. The released GOx improves the production efficiency of •OH to kill cancer cells for release of tumor-associated antigens via chemodynamic therapy (CDT). The enhanced immunogenic cell death (ICD) can activate the immunosuppressive tumor microenvironment and improve the immunotherapy effect of the released αPDL1, which significantly suppresses primary and metastatic tumors. Thus, the nanocomplexes with Fenton reaction-triggered protein release show great potentials to improve the immunotherapeutic efficacy of ICB via combination with CDT.

Covalent Organic Framework Nanocarriers of Singlet Oxygen for Oxygen-Independent Concurrent Photothermal/Photodynamic Therapy to Ablate Hypoxic Tumors.

Photodynamic therapy (PDT) of cancers is seriously restricted by tumor hypoxia. In addition to the intrinsic hypoxic microenvironment, continuous photoirradiation further aggravates intratumoral hypoxia, thereby reducing the PDT effect significantly. Oxygen-independent PDT is recognized as an efficient approach to overcome this issue. Herein, singlet oxygen (1 O2 )-stored covalent organic framework (COF) nanoparticles loading the near-infrared (NIR) dye cypate, which realize oxygen-independent 1 O2 production for concurrent photothermal therapy (PTT) and PDT under NIR irradiation, are presented. The cypate-loading COF nanoparticles are prepared by using the photosensitizers and 1 O2 -stored molecules via formation of Schiff base bonds, followed by coverage of poly(vinyl pyrrolidone). The COF nanoparticles significantly improve the photostability and photothermal conversion efficiency of cypate by protecting them from photodegradation under NIR irradiation. Upon 660 nm laser irradiation, 1 O2 is produced by the photosensitizer motifs and is successfully stored by the 1 O2 -stored moieties. After intravenous injection and tumor accumulation, the COF nanoparticles can generate heat quickly upon 808 nm irradiation which induces the efficient release of the stored 1 O2 to ablate tumors via O2 -independent concurrent PTT/PDT. Accordingly, the COF nanocarriers of 1 O2 provide a paradigm to develop O2 -independent concurrent PTT/PDT for precise cancer treatment upon NIR irradiation.

Glutathione-Triggered Mitochondria-Targeting Reassembly from Polymeric Micelles to Nanofibers for a Synergistic Anticancer Effect.

Nanofibers self-assembled from peptides have attracted much attention to inhibit cancer cells. However, there are still some disadvantages, including high concentration for self-assembly and incapability to load drugs, which limit their applications. In this report, we rationally integrate self-assembled peptides, glutathione-sensitive disulfide bonds, and mitochondrial targeting moieties into the amphiphilic block copolymer to construct the nanocarriers, which can be used to load anticancer drug doxorubicin (DOX). After cellular internalization, the nanocarriers can reassemble from micelles to nanofibers under the trigger by glutathione and locate in mitochondria. The released DOX and nanofibers induce mitochondrial dysfunction and activate the apoptosis pathway to synergistically inhibit tumor cells. This organelle-specific drug delivery system with reassembly capability from micelles to nanofibers shows great potential for effectively killing cancer cells.

Tumor-dilated polymersome nanofactories for enhanced enzyme prodrug chemo-immunotherapy.

Combination chemo-immunotherapy of cancers has attracted great attention due to its significant synergistic antitumor effect. The response rates and therapeutic efficacy of immunotherapy can be enhanced significantly after proper combination with chemotherapy. However, chemo-immunotherapy is frequently limited by severe immune-related adverse events and systemic side toxicity. In this report, efficient nanofactory-directed enzyme prodrug chemo-immunotherapy is demonstrated based on enzyme-loaded tumor-dilatable polymersomes with optimized membrane cross-linking density. Upon intravenous injection of the nanofactories, they can passively accumulate at the tumor site. The tumor pH-responsive nanofactories can swell from ~100 nm to ~200 nm under the trigger of tumor acidity, leading to prolonged retention of up to one week inside tumor tissues. Simultaneously, the membrane permeability of the nanofactories has improved significantly, which allows hydrophilic small molecules to pass across the membranes while keeping the enzymes in the inner cavities. Subsequently, the non-toxic prodrug mixtures of chemo-immunotherapy are administrated three times within 6 days, which are in situ activated by the nanofactories selectively at tumor sites. Activated chemotherapeutic drugs kill cancer cells and generate tumor-associated antigens to promote the maturation of dendritic cells. Activated indoleamine 2, 3-dioxygenase 1 inhibitors reverse the immunosuppressive tumor microenvironment. Finally, primary tumors can be effectively suppressed while causing minimal systemic toxicity. The distant tumors that are established after treatment can also be inhibited completely via activation of antitumor immunity in mice. Thus, the tumor-dilatable polymersome nanofactories with long-term intratumoral retention offer a promising paradigm for enhanced enzyme prodrug chemo-immunotherapy.

Hypoxia-Responsive Polyprodrug Nanocarriers for Near-Infrared Light-Boosted Photodynamic Chemotherapy.

The hypoxia environment inside tumors is tightly associated with tumor growth, metastasis, and drug resistance. However, the heterogonous distribution of hypoxic areas limits the efficacy of hypoxia-activatable drug delivery systems. Herein, we report the hypoxia-activable block copolymer polyprodrugs, which are composed of poly(ethylene glycol) (PEG) and copolymerized segments of ortho-nitrobenzyl-linked camptothecin (CPT) methacrylate and 2-(piperidin-1-yl)ethyl methacrylate (PEMA) monomers. After self-assembly in aqueous solution, indocyanine green (ICG) photosensitizers were encapsulated to formulate ICG-loaded micellar nanoparticles (ICG@CPTNB) for near-infrared (NIR) light-boosted photodynamic therapy (PDT), tumor hypoxia aggravation, and responsive drug activation. Through intravenous injection and prolonged blood circulation, the nanoparticles can accumulate into tumor efficiently. Tumor acidity-triggered charge transition of PEMA units remarkably promotes cellular internalization of the nanoparticles. Upon exposure to NIR laser irradiation, ICG inside the nanoparticles produced reactive oxygen species (ROS) along with local hypothermia. Simultaneously, the oxygen consumption during ROS production aggravated the intratumoral hypoxia, which amplified hypoxia-responsive self-immolative CPT release from the nanoparticles. The combined photodynamic chemotherapy using hypoxia-responsive polyprodrug nanoparticles, ICG@CPTNB, overcomes the limitations of single therapy of hypoxia-activable prodrugs or PDT, which remarkably improves the efficiency of tumor growth suppression.

Enzymatically Transformable Polymersome-Based Nanotherapeutics to Eliminate Minimal Relapsable Cancer.

Prevention of metastatic and local-regional recurrence of cancer after surgery remains difficult. Targeting postsurgical premetastatic niche and microresiduals presents an excellent prospective opportunity but is often challenged by poor therapeutic delivery into minimal residual tumors. Here, an enzymatically transformable polymer-based nanotherapeutic approach is presented that exploits matrix metalloproteinase (MMP) overactivation in tumor-associated tissues to guide the codelivery of colchicine (microtubule-disrupting and anti-inflammatory agent) and marimastat (MMP inhibitor). The dePEGylation of polymersomes catalyzed by MMPs not only exposes the guanidine moiety to improve tissue/cell-targeting/retention to increase bioavailability, but also differentially releases marimastat and colchicine to engage their extracellular (MMPs) and intracellular (microtubules) targets of action, respectively. In primary tumors/overt metastases, the vasculature-specific targeting of nanotherapeutics can function synchronously with the enhanced permeability and retention effect to deter malignant progression of metastatic breast cancer. After the surgical removal of large primary tumors, nanotherapeutic agents are localized in the premetastatic niche and at the site of the postsurgical wound, disrupting the premetastatic microenvironment and eliminating microresiduals, which radically reduces metastatic and local-regional recurrence. The findings suggest that nanotherapeutics can safely widen the therapeutic window to resuscitate colchicine and MMP inhibitors for other inflammatory disorders.