Dual-sensitive dual-prodrug nanoparticles with light-controlled endo/lysosomal escape for synergistic photoactivated chemotherapy.

The clinical application of conventional chemotherapeutic agents, represented by cisplatin, is limited by severe side effects. So, it is essential to explore more safer and controlled drug delivery systems for synergistic chemotherapy. In this work, we designed dual-sensitive dual-prodrug nanoparticles (DDNPs) for photoactivated platinum-based synergistic chemotherapy. With photosensitivity, DDNPs could be photoactivated from inert Pt(IV) to toxic Pt(II) under safe UVA light in a spatiotemporally controlled manner. Concurrently, mild could be generated from DDNPs to assist the endo/lysosomal escape of DDNPs for better photoactivated chemotherapy (PACT). Furthermore, with acid-sensitivity, demethylcantharidin (DMC), a protein phosphatase 2A (PP2A) inhibitor, was released to block the DNA repair pathway and thereby could sensitize platinum-based chemotherapy in intracellular acidic microenvironments. Along with a precise ratio (Pt : DMC = 1 : 2), DDNPs had a powerful synergistic anti-cancer effect in vitro and in vivo. In the future, DDNPs have great potential as a safe and multifunctional drug delivery system for precise nanomedicine in clinical treatments.

Reduction-Sensitive Fluorinated-Pt(IV) Universal Transfection Nanoplatform Facilitating CT45-Targeted CRISPR/dCas9 Activation for Synergistic and Individualized Treatment of Ovarian Cancer.

Compared to traditional clustered regularly interspaced short palindromic repeat (CRISPR)/CRISPR-associated protein 9 (Cas9) system, CRISPR/dead Cas9 (dCas9) system can precisely regulate endogenous gene expression without damaging the host gene, representing a greater potential for cancer therapy. Cancer/testis antigen 45 (CT45) is proved to enhance platinum-based chemosensitivity for individualized ovarian cancer therapy. However, the development of a single nanocarrier codelivering CRISPR/dCas9 system and chemotherapeutics for synergistic cancer therapy still faces challenges. Herein, a reduction-sensitive fluorinated-Pt(IV) universal transfection nanoplatform (PtUTP-F) is developed for the CT45-targeted CRISPR/dCas9 activation to achieve synergistic and individualized treatment of ovarian cancer. Overcoming multiple physiological barriers, PtUTP-F condensed gene can efficiently transfect into different cells including 293T cells, A2780, SKOV3, A549, and A2780/cisplatin (DDP) cancer cells, which is superior to Lipofectamine 6000. With the responsive release of gene and Pt(II) in the intracellular reducing microenvironment, PtUTP-F/dCas9-CT45 can generate CRISPR/dCas9 activation of CT45 expression for protein phosphatase 4C (PP4C) activity inhibition to hinder the DNA repair pathway and thus enhances the sensitivity to Pt(II) drugs for individualized A2780 tumor therapy. The PtUTP-F not only represents a powerful nanoplatform for CRISPR/dCas9 system delivery but also initiates a novel strategy for synergistic and individualized treatment of CRISPR/dCas9-based gene therapy with chemotherapy.

Near-Infrared Light-Triggered Polyprodrug/siRNA Loaded Upconversion Nanoparticles for Multi-Modality Imaging and Synergistic Cancer Therapy.

Stimuli-responsive nanosystems have been widely applied as effective modalities for drug/gene co-delivery in cancer treatment. However, precise spatiotemporal manipulations of drug/gene co-delivery, as well as multi-modality imaging-guided cancer therapy, still remain a daunting challenge. Here, multifunctional polyprodrug/siRNA loaded upconversion nanoparticles (UCNPs) are reported that combine computed tomography (CT), magnetic resonance (MR), and upconversion luminescence (UCL) tri-modality imaging and near-infrared (NIR) light-activated drug/gene on-demand delivery. The photoactivatable platinum(IV) (Pt(IV))-backbone polymers (PPt) and the siRNA targeting polo-like kinase 1 (Plk1) are loaded on the surface of polyethyleneimine (PEI)-coated UCNPs (PUCNP) to obtain the multifunctional polyprodrug/siRNA loaded UCNPs (PUCNP@Pt@siPlk1). The PUCNP@Pt@siPlk1 can be served as a "nanotransducer" to convert NIR light (980 nm) into local ultraviolet (UV) to visible light for the cleavage of photosensitive PPt, resulting in the simultaneous on-demand release of high toxic platinum(II) (Pt(II)) and siPlk1. Meanwhile, the PUCNP@Pt@siPlk1 has CT, T1 -weighted MR, and UCL tri-modality imaging abilities. Based on these merits, PUCNP@Pt@siPlk1 displayed excellent synergistic therapeutic efficacy via image-guided and NIR light-activated platinum-based chemotherapy and RNA interfering in vitro and in vivo. Thus, this developed nanosystem with NIR light-controlled drug/gene delivery and multi-modality imaging abilities, will display great potential in combining chemotherapy and gene therapy.

Dual Cross-linked HHA Hydrogel Supplies and Regulates MΦ2 for Synergistic Improvement of Immunocompromise and Impaired Angiogenesis to Enhance Diabetic Chronic Wound Healing.

Immunocompromise and impaired angiogenesis of diabetes lead to chronic inflammation when wounds occur, which is the primary reason for the long-term incurable nature of diabetic chronic wounds. Herein, a high-molecular-weight hyaluronic acid (HHA) hydrogel is developed to supply and regulate M2 phenotype macrophages (MΦ2) for synergistic improvement of immunocompromise and impaired angiogenesis. MΦ2 are seeded on the Cu-HHA/PVA hydrogels prepared by Cu2+ cross-linking of low degree and physical cross-linking (one freeze-thaw cycle and unique lyophilization) to form Cu-HHA/PVA@MΦ2 hydrogels. The Cu-HHA/PVA@MΦ2 hydrogel can directly supply the MΦ2 in the wound site, maintain the consistent phenotype of loaded MΦ2, and transform the M1 phenotype macrophages (MΦ1) in the wound bed to MΦ2 by HHA. Furthermore, Cu2+ could be released from the hydrogels to further stimulate angiogenesis, thus accelerating the wound-healing phase transition from inflammation to proliferation and remodeling. The average wound area after the 0.5Cu-HHA/PVA@MΦ2 (ionic cross-linking degree 0.5%) treatment was much smaller than that of other diabetic groups at day 12 and close to that of the wild nondiabetic control group. Therefore, this facile hydrogel strategy with multiple modulation mechanisms of immunocompromise and angiogenesis may act as a safe and effective treatment strategy for a diabetic chronic wound.

Morphology tunable and acid-sensitive dextran-doxorubicin conjugate assemblies for targeted cancer therapy.

Stimuli-responsive and targetable nanomedicine systems have been widely applied as effective modalities for drug delivery and tumor therapeutics. Particle shape is also important for the biodistribution and cellular uptake in drug delivery applications. Here, morphology tunable and acid-responsive dextran-doxorubicin conjugate assemblies of DD-M and DDF-V for targeted doxorubicin (DOX) delivery were constructed, which contain the following favorable advantages: (1) one-pot synthesis of the drug loaded system with a Schiff base reaction is a green chemistry method which is better than the conventional drug conjugation/encapsulation methods. (2) The morphology of the nanoparticles could be regulated from a micelle (DD-M) to vesicle (DDF-V) structure by either introducing folic acid (FA) or not. (3) The abundant hydroxyl groups and electronegativity give DD-M and DDF-V superior stability in the physiological environment. (4) Besides, the multifunctional DDF-V with its important merits including tumor-targeting ability and acid-responsiveness is specific for DOX delivery in cancer therapy. (5) Compared to free DOX and DD-M, DDF-V displayed enhanced anti-tumor efficacy both in vitro and in vivo without obvious systematic toxicity. The morphology tunable, acid-sensitive and targetable nanosystem could be a promising strategy for site-specific drug delivery and potential cancer therapy in the future.

Absorbable Thioether Grafted Hyaluronic Acid Nanofibrous Hydrogel for Synergistic Modulation of Inflammation Microenvironment to Accelerate Chronic Diabetic Wound Healing.

Current standard of care dressings are unsatisfactorily inefficacious for the treatment of chronic wounds. Chronic inflammation is the primary cause of the long-term incurable nature of chronic wounds. Herein, an absorbable nanofibrous hydrogel is developed for synergistic modulation of the inflammation microenvironment to accelerate chronic diabetic wound healing. The electrospun thioether grafted hyaluronic acid nanofibers (FHHA-S/Fe) are able to form a nanofibrous hydrogel in situ on the wound bed. This hydrogel degrades and is absorbed gradually within 3 days. The grafted thioethers on HHA can scavenge the reactive oxygen species quickly in the early inflammation phase to relieve the inflammation reactions. Additionally, the HHA itself is able to promote the transformation of the gathered M1 macrophages to the M2 phenotype, thus synergistically accelerating the wound healing phase transition from inflammation to proliferation and remodeling. On the chronic diabetic wound model, the average remaining wound area after FHHA-S/Fe treatment is much smaller than both that of FHHA/Fe without grafted thioethers and the control group, especially in the early wound healing stage. Therefore, this facile dressing strategy with intrinsic dual modulation mechanisms of the wound inflammation microenvironment may act as an effective and safe treatment strategy for chronic wound management.

Photoactivatable Prodrug-Backboned Polymeric Nanoparticles for Efficient Light-Controlled Gene Delivery and Synergistic Treatment of Platinum-Resistant Ovarian Cancer.

Combination of chemotherapy and gene therapy provides an effective strategy for cancer treatment. However, the lack of suitable codelivery systems with efficient endo/lysosomal escape and controllable drug release/gene unpacking is the major bottleneck for maximizing the combinational therapeutic efficacy. In this work, we developed a photoactivatable Pt(IV) prodrug-backboned polymeric nanoparticle system (CNPPtCP/si(c-fos)) for light-controlled si(c-fos) delivery and synergistic photoactivated chemotherapy (PACT) and RNA interference (RNAi) on platinum-resistant ovarian cancer (PROC). Upon blue-light irradiation (430 nm), CNPPtCP/si(c-fos) generates oxygen-independent N3• with mild oxidation energy for efficient endo/lysosomal escape through N3•-assisted photochemical internalization with less gene deactivation. Thereafter, along with Pt(IV) prodrug activation, CNPPtCP/si(c-fos) dissociates to release active Pt(II) and unpack si(c-fos) simultaneously. Both in vitro and in vivo results demonstrated that CNPPtCP/si(c-fos) displayed excellent synergistic therapeutic efficacy on PROC with low toxicity. This PACT prodrug-backboned polymeric nanoplatform may provide a promising gene/drug codelivery tactic for treatment of various hard-to-tackle cancers.

Photostability Highly Improved Nanoparticles Based on IR-780 and Negative Charged Copolymer for Enhanced Photothermal Therapy.

The development of near-infrared (NIR) dyes with desirable photophysical characteristics for tumor therapy is highly expected at present. In this report, IR-780 iodide was loaded by the mercaptopropionic acid grafted poly(ethylene glycol)-block-poly(ε-caprolactone)-block-poly(allyl glycidyl ether) [mPEG5K-PCL10K-PAGE6 (MPA)] copolymer to form nanomicelles (IR-780@TBMPA) in aqueous solution. On account of the hydrophobic and electrostatic interaction between mPEG5K-PCL10K-PAGE6 (MPA) and IR-780, the IR-780@TBMPA micelle was structurally stable with improved solubility, light stability and biocompatibility. The encapsulation of IR-780 indicated no influence on its original physicochemical property, showing good optical and thermal characteristics. The drug-loaded micelles had appropriate microscopic size for endocytosis, displaying significant cytotoxicity to HeLa cells under NIR laser irradiation. In addition, the phototoxicity generated by photothermal and photodynamic effect of IR-780@TBMPA under 808 nm laser irradiation was also investigated by reactive oxygen species (ROS) detection and flow cytometry. Furthermore, the superior accumulation of IR-780@TBMPA in tumor tissues provided sufficient hyperthermia to kill tumor cells, indicating its potential in cancer clinical therapy.

[Relationship between opposite acupoints and acupoint effect from acupoint effect of Sanyinjiao (SP 6)-Xuanzhong (GB 39)].

The acupoint effect of Sanyinjiao (SP 6) and Xuanzhong (GB 39) as well as the internal relation of Sanyinjiao (SP 6)-Xuanzhong (GB 39) were analyzed in this paper to explore the relationship between opposite acupoints and acupoint effect. It was found both Sanyinjiao (SP 6) and Xuanzhong (GB 39) had acupoint effects, and the two acupoints had close relationship in acupoint effects (specificity along meridian and specificity of acupoints), acupoint-meridian relationship (anatomical locations, meridians and organs, indications). It is indicated the opposite acupoint of Sanyinjiao (SP 6)-Xuanzhong (GB 39) had related aspects in acupoint effects, which is related with acupoint effect through specificity and relationship of acupoint-meridian.