Bortezomib prodrug catalytic nanoreactor for chemo/chemodynamic therapy and macrophage re-education.

Chemodynamic therapy (CDT), an emerging tumor-specific therapeutic modality, is frequently restrained by insufficient intratumoral Fenton catalysts and increasingly inefficient catalysis caused by the continuous consumption of limited H2O2 within tumors. Herein, we engineered a pH-responsive bortezomib (BTZ) polymer prodrug catalytic nanoreactor (HeZn@HA-BTZ) capable of self-supplying Fenton catalyst and H2O2. It is aimed for tumor-specific chemo/chemodynamic therapy via oxidative stress and endoplasmic reticulum (ER) stress dual-amplification and macrophage repolarization. A catechol­boronate bond-based hyaluronic acid-BTZ prodrug HA-DA-BTZ was modified on Hemin and Zn2+ coordination nanoscale framework (HeZn), an innovative CDT inducer, to construct He-Zn@HA-BTZ. He-Zn@HA-BTZ with good stability and superior peroxidase-like activity preferentially accumulated at tumor sites and be actively internalized by tumor cells. Under the cleavage of catechol­boronate bond in acidic endo/lysosomes, pre-masked BTZ was rapidly released to induce ubiquitinated protein aggregation, robust ER stress and elevated H2O2 levels. The amplified H2O2 was further catalyzed by HeZn via Fenton-catalytic reactions to produce hypertoxic •OH, enabling cascaded oxidative stress amplification and long-lasting effective CDT, which in turn aggravated BTZ-induced ER stress. Eventually, a dual-amplification of oxidative stress and ER stress was achieved to initiate cell apoptosis/necrosis with reduced BTZ toxicity. Intriguingly, He-Zn@HA-BTZ could repolarize macrophages from M2 to antitumor M1 phenotype for potential tumor therapy. This "all in one" prodrug nanocatalytic reactor not only enriches the CDT inducer library, but provides inspirational strategy for simultaneous oxidative stress and ER stress based excellent cancer therapy.

Fibroblast activation protein α activatable theranostic pro-photosensitizer for accurate tumor imaging and highly-specific photodynamic therapy.

The development of activatable photosensitizers (aPSs) responding to tumor-specific biomarkers for precision photodynamic therapy (PDT) is urgently required. Due to the unique proteolytic activity and highly restricted distribution of tumor-specific enzymes, enzyme activatable photosensitizers display superior selectivity. Methods: Herein, a series of novel Fibroblast Activation Protein α (FAPα) activatable theranostic pro-photosensitizers were designed by conjugating the different N-terminal blocked FAPα-sensitive dipeptide substrates with a clinical PS, methylene blue (MB), through a self-immolative linker, which resulting in the annihilation of the photoactivity (fluorescence and phototoxicity). The best FAPα-responsive pro-photosensitizer was screened out through hydrolytic efficiency and blood stability. Subsequently, a series of in vitro and in vivo experiments were carried out to investigate the FAPα responsiveness and enhanced PDT efficacy. Results: The pro-photosensitizers could be effectively activated by tumor-specific FAPα in the tumor sites. After response to FAPα, the "uncaged" MB can recover its fluorescence and phototoxicity for tumor imaging and cytotoxic singlet oxygen (1O2) generation, eventually achieving accurate imaging-guided PDT. Simultaneously, the generated azaquinone methide (AQM) could serve as a glutathione (GSH) scavenger to rapidly and irreversibly weaken intracellular antioxidant capacity, realizing synergistic oxidative stress amplification and enhanced PDT effect. Conclusion: This novel FAPα activatable theranostic pro-photosensitizers allow for accurate tumor imaging and admirable PDT efficacy with minimal systemic side effects, offering great potential in clinical precision antitumor application.

A DNA damage nanoamplifier for the chemotherapy of triple-negative breast cancer via DNA damage induction and repair blocking.

Due to a powerful DNA damage repair system and a lack of surface markers, there is currently no effective chemotherapy or tailored targeted therapies available for triple-negative breast cancer (TNBC) treatment. Herein, a tailored DNA damage nanoamplifier (Lipo@Nir/Pt(IV)C18) was engineered to simultaneously induce DNA damage and inhibit DNA reparation for highly efficient TNBC treatment. A newly synthesized Pt(IV)C18 prodrug, the DNA damaging inducer, and the hydrophobic poly(ADP-ribose) polymerases (PARPs) inhibitor niraparib, which is used as the DNA repair blocker, were concurrently encapsulated in highly biocompatible PEGylated liposomes to prepare Lipo@Nir/Pt(IV)C18, for enhanced cancer therapy and future clinical translation. Lipo@Nir/Pt(IV)C18 with an appropriate size and excellent stability, effectively accumulated at the tumor site. After internalization by tumor cells, niraparib, a highly-selective hydrophobic PARP1 inhibitor, could exacerbate the accumulation of platinum-induced DNA lesions to induce excessive genome damage for synergistic cell apoptosis, which was evidenced by the upregulated γ-H2AX and cleaved-PARP levels. Importantly, Lipo@Nir/Pt(IV)C18 exhibited remarkable antitumor efficacy on TNBC without BRCA mutants in vivo with little systemic toxicity. Inspired by the concept of "synthetic lethality", this study provides an inspirational and clinically transformable nanobased DNA damaging amplification strategy for the expansion of TNBC beneficiaries and highly efficient TNBC treatment via DNA damage induction and DNA repair blocking.

Reactive oxygen species-activatable self-amplifying Watson-Crick base pairing-inspired supramolecular nanoprodrug for tumor-specific therapy.

Intratumoral upregulated reactive oxygen species (ROS) has been extensively exploited as exclusive stimulus to activate drug release for tumor-specific therapy. However, insufficient endogenous ROS and tumor heterogeneity severely restrict clinical translation of current ROS-responsive drug delivery systems. Herein, a tailored ROS-activatable self-amplifying supramolecular nanoprodrug was developed for reinforced ROS-responsiveness and highly selective antitumor therapy. A novel ROS-cleavable CA-based thioacetal linker CASOH was synthesized with ROS generator cinnamaldehyde (CA) incorporated into its molecular structure, to skillfully realize self-amplifying positive feedback loop of "ROS-activated CA release with CA-induced ROS regeneration". CASOH was modified with a cytosine analogue gemcitabine (GEM) to obtain ROS-activatable self-immolative prodrug CAG, which could be selectively activated in tumor cells and further achieve self-boosting "snowballing" activation via ROS compensation, while keep inactive in normal cells. Through Watson-Crick nucleobase pairing (G≡C)-like hydrogen bonds, CAG efficiently crosslinked with a matched guanine-rich acyclovir-modified hyaluronic acid conjugate HA-ACV, to self-assemble into pH/ROS dual-responsive supramolecular nanoprodrug HCAG. With high stability, beneficial tumor targeting capacity and pH/ROS-responsiveness, HCAG nanoformulation exhibited remarkable in vivo antitumor efficacy with minimal systemic toxicity. Based on unique tumor-specific self-amplifying prodrug activation and Watson-Crick base pairing-inspired supramolecular self-assembly, this study provides an inspirational strategy of exploiting novel ROS-responsive nanoplatform with reinforced responsiveness and specificity for future clinical translation.

Discovery of a Potent Glutathione Peroxidase 4 Inhibitor as a Selective Ferroptosis Inducer.

Potent and selective ferroptosis regulators promote an intensive understanding of the regulation and mechanisms underlying ferroptosis, which is highly associated with various diseases. In this study, through a stepwise structure optimization, a potent and selective ferroptosis inducer was developed targeting to inhibit glutathione peroxidase 4 (GPX4), and the structure-activity relationship (SAR) of these compounds was uncovered. Compound 26a exhibited outstanding GPX4 inhibitory activity with a percent inhibition up to 71.7% at 1.0 µM compared to 45.9% of RSL-3. At the cellular level, 26a could significantly induce lipid peroxide (LPO) increase and effectively induce ferroptosis with satisfactory selectivity (the value of 31.5). The morphological analysis confirmed the ferroptosis induced by 26a. Furthermore, 26a significantly restrained tumor growth in a mouse 4T1 xenograft model without obvious toxicity.

[UPLC characteristic fingerprint and chemical pattern recognition of Angong Niuhuang Pills].

To establish the UPLC fingerprint of Zhongyi Angong Niuhuang Pills, in order to evaluate its quality by chemical pattern recognition. The method was developed on a column of Poroshell 120 EC-C_(18), with methanol-0.1% formic acid solution as the mobile phase for gradient elution at a flow rate of 0.4 mL·min~(-1). The column temperature was 30 ℃,and the detective wavelength was 254 nm. The similarity of 24 batches of Angong Niuhuang Pills was compared by using Traditional Chinese Medicine Chromatographic Fingerprint Similarity Evaluation System(2004 A). Hydrophobic cluster analysis,principal components analysis and partial least squares discriminant analysis were conducted by using SIMCA 13.0 software to investigate different components among these products. The UPLC characteristic fingerprint was established in this study. And 17 common peaks were identified by standard reference and UPLC-MS. The similarity of 24 batches samples were above 0.980,which can be classified into three categories for pattern recognition. Baicalin,berberine,jatrorrhizine,wogonin and wogonoside were identified as the main markers that cause differences of various batches. The method is simple,rapid,accurate and reproducible,and can provide scientific basis for improving the quality standard of Zhongyi Angong Niuhuang Pills.

Phthalocyanine-based coordination polymer nanoparticles for enhanced photodynamic therapy.

In the photodynamic therapy (PDT) of cancer, zinc phthalocyanine (ZnPc) as a photosensitizer possesses superior photosensitive properties. However, the therapeutic effect of ZnPc in PDT is limited due to its aggregation, low solubility and poor selectivity. In this study, charge-reversal phthalocyanine-based coordination polymer nanoparticles (PCPN) are developed for improving the curative effect of ZnPc. Tetra(4-carboxyphenoxy)-phthalocyaninatozinc(ii) (TPZnPc) is coordinated with the zinc ion to form the core of PCPN, which is coated with a lipid bilayer by self-assembly (PCPNs@Lip). TPZnPc molecules in the core of PCPN are in the monomeric state and can generate cytotoxic singlet oxygen (1O2) efficiently, which solves the solubility and aggregation problems of ZnPc. Meanwhile, 1,2-dicarboxylic-cyclohexane anhydride modified lysyl-cholesterol (DLC) is functionalized on the surface of PCPN (PCPNs@Lip/DLC), endowing PCPN with a charge-reversal ability which could be triggered by a mildly acidic tumor microenvironment. PCPNs@Lip/DLC is proved to enhance tumor cellular uptake and generate more intracellular 1O2 after irradiation. As confirmed by in vitro and in vivo studies, PCPNs@Lip/DLC remarkably increases the PDT effect. All these results demonstrate that PCPNs@Lip/DLC is a promising nanoplatform for the application of ZnPc in effective PDT.

Bisphosphonate-functionalized coordination polymer nanoparticles for the treatment of bone metastatic breast cancer.

Bone is the most common organ affected by metastatic breast cancer. Targeting cancers within the bone remains a great challenge due to the inefficient delivery of therapeutic to bone. In this study, a polyethylene glycol (PEG) coated nanoparticles (NPs) made of a Zn2+ coordination polymer was linked with a bone seeking moiety, alendronate (ALN), to deliver cisplatin prodrug (DSP) to the bone. The particle sizes of this novel system, DSP-Zn@PEG-ALN NPs, were regulated by adjusting the volume ratio of water phase to oil phase in microemulsion. It was small enough (about 55nm) to extravasate through the clefts (80nm) of the bone's sinusoidal capillaries and localize into metastatic bones. DSP-Zn@PEG-ALN NPs showed much higher affinity for hydroxyapatite in vitro and bone in vivo than non-targeted DSP-Zn@PEG NPs and cisplatin. In addition, the in vivo biodistribution studies demonstrated that about 4-fold of platinum was delivered to the bone metastatic lesions than that in healthy bones by DSP-Zn@PEG-ALN NPs intravenously. Finally, DSP-Zn@PEG-ALN NPs not only inhibited the tumor growth efficiently but also reduced the osteocalastic bone destruction. Besides, DSP-Zn@PEG-ALN NPs showed significantly reduced toxicity of cisplatin. These results indicate that the DSP-Zn@PEG-ALN NPs have a great potential in enhancing chemotherapeutic efficacy for the treatment of bone metastatic breast cancer.

Coordination self-assembly of platinum-bisphosphonate polymer-metal complex nanoparticles for cisplatin delivery and effective cancer therapy.

Cisplatin (CDDP) is a potent anti-carcinogen that is widely used for various solid tumors; however, its clinical application is limited by its severe nephrotoxicity. Novel platinum-bisphosphonate polymer-metal complex nanoparticles (Pt-bp NPs), based on platinum-bisphosphonate coordination, have been established. Three polymer carriers bearing alendronate (ALN) ligands, while containing different lengths of alkyl hydrophobic chains, were synthesized. Their structures were characterized by 1H NMR, 31P NMR and FTIR. The ALN was used to coordinate to the CDDP precursor [Pt(NH3)2(OSO3)(OH2)], and the Pt-bp NPs were formed spontaneously. The Pt-bp NPs formed by the polymer carrier, ALN-PEG2k-ASAC18, which contained the poly(ethylene glycol) chain with ALN on one side and the octadecyl hydrophobic chain on the other side, was denoted as ALN-ASAC18-CDDP; its diameter was within 200 nm. CDDP was released in a Cl- or pH-dependent manner. The cytotoxic effects to the HeLa, A549 and MCF-7 cell lines were relatively weak, compared to CDDP. However, ALN-ASAC18-CDDP showed significantly prolonged blood circulation time and tumor accumulation of platinum of 2.5-fold, compared to CDDP at 8 h. Besides, ALN-ASAC18-CDDP was demonstrated to remarkably reduce systemic toxicity without compromising in vivo antitumor activity. These results indicate that the facilely prepared ALN-ASAC18-CDDP has great utilization potential for CDDP delivery in a clinical setting.

A novel capsular tension ring as local sustained-release carrier for preventing posterior capsule opacification.

One of the most important and challenging goals in pharmaceutical prevention for posterior capsule opacification is to preserve an effective drug concentration in capsular bag for a long period without affecting the patients' vision. Here, a novel kind of composite, which was prepared by 2-hydroxyethyl methacrylate (HEMA) and methyl methacrylate (MMA) via a two-step process, was applied for capsular tension ring (CTR) as an implant that could deliver docetaxel (DTX) over a long period of time. The drug release rate of the composite could be controlled by the ethyleneglycol dimethacrylate (EGDMA) content and the ratio of HEMA/MMA as well as the structure of porous PMMA framework. The CTR could continuously release DTX for up to 6 weeks in vitro and maintain DTX in effective concentration in the aqueous humor after 42 days. Docetaxel-load capsular tension ring (DTX-CTR) presented strong inhibition on the lens epithelial cells in-vivo without obvious damage to normal tissues. These results indicate that the drug sustained-release CTR can provide a promising application in posterior capsule opacification prevention.

Laser-triggered intraocular implant to induce photodynamic therapy for posterior capsule opacification prevention.

Posterior capsule opacification (PCO) is one of the main reasons for loss of vision again after cataract surgery. In this study, intraocular lenses were modified with indocyanine green (ICG) and sealed up with PLGA to form long-term intraocular implants (ICG-IOL). When triggered by laser, ICG-IOL would induce photodynamic therapy (PDT). In-vitro cell viability assay and scratch wound healing assay demonstrated that ICG-IOL could effectively inhibit HLEpiC proliferation and migration without causing damage to the cells far away from it. Laser attenuation test indicated that ICG-IOL could be applied in vivo. In-vivo pharmacodynamics and safety study showed that ICG-IOL could significantly prevent the occurrence of PCO and was safe for intraocular normal tissue. All these results suggested that ICG-IOL would be a very promising candidate for PCO prevention.