Epsin Nanotherapy Regulates Cholesterol Transport to Fortify Atheroma Regression.

BACKGROUND: Excess cholesterol accumulation in lesional macrophages elicits complex responses in atherosclerosis. Epsins, a family of endocytic adaptors, fuel the progression of atherosclerosis; however, the underlying mechanism and therapeutic potential of targeting Epsins remains unknown. In this study, we determined the role of Epsins in macrophage-mediated metabolic regulation. We then developed an innovative method to therapeutically target macrophage Epsins with specially designed S2P-conjugated lipid nanoparticles, which encapsulate small-interfering RNAs to suppress Epsins. METHODS: We used single-cell RNA sequencing with our newly developed algorithm MEBOCOST (Metabolite-mediated Cell Communication Modeling by Single Cell Transcriptome) to study cell-cell communications mediated by metabolites from sender cells and sensor proteins on receiver cells. Biomedical, cellular, and molecular approaches were utilized to investigate the role of macrophage Epsins in regulating lipid metabolism and transport. We performed this study using myeloid-specific Epsin double knockout (LysM-DKO) mice and mice with a genetic reduction of ABCG1 (ATP-binding cassette subfamily G member 1; LysM-DKO-ABCG1fl/+). The nanoparticles targeting lesional macrophages were developed to encapsulate interfering RNAs to treat atherosclerosis. RESULTS: We revealed that Epsins regulate lipid metabolism and transport in atherosclerotic macrophages. Inhibiting Epsins by nanotherapy halts inflammation and accelerates atheroma resolution. Harnessing lesional macrophage-specific nanoparticle delivery of Epsin small-interfering RNAs, we showed that silencing of macrophage Epsins diminished atherosclerotic plaque size and promoted plaque regression. Mechanistically, we demonstrated that Epsins bound to CD36 to facilitate lipid uptake by enhancing CD36 endocytosis and recycling. Conversely, Epsins promoted ABCG1 degradation via lysosomes and hampered ABCG1-mediated cholesterol efflux and reverse cholesterol transport. In a LysM-DKO-ABCG1fl/+ mouse model, enhanced cholesterol efflux and reverse transport due to Epsin deficiency was suppressed by the reduction of ABCG1. CONCLUSIONS: Our findings suggest that targeting Epsins in lesional macrophages may offer therapeutic benefits for advanced atherosclerosis by reducing CD36-mediated lipid uptake and increasing ABCG1-mediated cholesterol efflux.

Targeting Epsins to Inhibit Fibroblast Growth Factor Signaling While Potentiating Transforming Growth Factor-ß Signaling Constrains Endothelial-to-Mesenchymal Transition in Atherosclerosis.

BACKGROUND: Epsin endocytic adaptor proteins are implicated in the progression of atherosclerosis; however, the underlying molecular mechanisms have not yet been fully defined. In this study, we determined how epsins enhance endothelial-to-mesenchymal transition (EndoMT) in atherosclerosis and assessed the efficacy of a therapeutic peptide in a preclinical model of this disease. METHODS: Using single-cell RNA sequencing combined with molecular, cellular, and biochemical analyses, we investigated the role of epsins in stimulating EndoMT using knockout in Apoe-/- and lineage tracing/proprotein convertase subtilisin/kexin type 9 serine protease mutant viral-induced atherosclerotic mouse models. The therapeutic efficacy of a synthetic peptide targeting atherosclerotic plaques was then assessed in Apoe-/- mice. RESULTS: Single-cell RNA sequencing and lineage tracing revealed that epsins 1 and 2 promote EndoMT and that the loss of endothelial epsins inhibits EndoMT marker expression and transforming growth factor-ß signaling in vitro and in atherosclerotic mice, which is associated with smaller lesions in the Apoe-/- mouse model. Mechanistically, the loss of endothelial cell epsins results in increased fibroblast growth factor receptor-1 expression, which inhibits transforming growth factor-ß signaling and EndoMT. Epsins directly bind ubiquitinated fibroblast growth factor receptor-1 through their ubiquitin-interacting motif, which results in endocytosis and degradation of this receptor complex. Consequently, administration of a synthetic ubiquitin-interacting motif-containing peptide atheroma ubiquitin-interacting motif peptide inhibitor significantly attenuates EndoMT and progression of atherosclerosis. CONCLUSIONS: We conclude that epsins potentiate EndoMT during atherogenesis by increasing transforming growth factor-ß signaling through fibroblast growth factor receptor-1 internalization and degradation. Inhibition of EndoMT by reducing epsin-fibroblast growth factor receptor-1 interaction with a therapeutic peptide may represent a novel treatment strategy for atherosclerosis.

Hydrogels for RNA delivery.

RNA-based therapeutics have shown tremendous promise in disease intervention at the genetic level, and some have been approved for clinical use, including the recent COVID-19 messenger RNA vaccines. The clinical success of RNA therapy is largely dependent on the use of chemical modification, ligand conjugation or non-viral nanoparticles to improve RNA stability and facilitate intracellular delivery. Unlike molecular-level or nanoscale approaches, macroscopic hydrogels are soft, water-swollen three-dimensional structures that possess remarkable features such as biodegradability, tunable physiochemical properties and injectability, and recently they have attracted enormous attention for use in RNA therapy. Specifically, hydrogels can be engineered to exert precise spatiotemporal control over the release of RNA therapeutics, potentially minimizing systemic toxicity and enhancing in vivo efficacy. This Review provides a comprehensive overview of hydrogel loading of RNAs and hydrogel design for controlled release, highlights their biomedical applications and offers our perspectives on the opportunities and challenges in this exciting field of RNA delivery.

The effect of internal orifice narrowing in laparoscopic inguinoscrotal hernia repair to prevent seroma formation: a prospective double-blind randomized controlled trial.

OBJECTIVES: Seroma represents the most prevalent postoperative complication following laparoscopic inguinal hernia repair, particularly in the case of large inguinoscrotal hernias. This randomized controlled trial was undertaken with the objective of assessing the effects of internal orifice narrowing achieved by suturing the divided distal hernia sac in laparoscopic repair of indirect inguinoscrotal hernias. METHODS: A total of 58 patients aged 18 years or older, were randomized into two groups: Group I, which underwent internal orifice narrowing, and Group II, which served as the control without narrowing. The study's primary endpoint was the incidence and volume of seroma in the inguinal region on postoperative days 1 and 7, as well as at 1, 3, and 6 months following the procedure. Secondary outcomes encompassed metrics like total operative time, acute and chronic pain levels, duration of hospital stay, recurrence rates, and the occurrence of any additional complications. RESULTS: In comparison to the control group, the experimental group exhibited a significantly lower incidence of seroma formation at 7 days (P = 0.001). Furthermore, the ultrasonic assessment indicated a reduced seroma volume in the operative group on postoperative day 7 (8.84 ± 17.71 vs. 52.39 ± 70.78 mL; P < 0.001). Acute pain levels and hospital stay were similar between the two groups (1.22 ± 0.76 vs. 1.04 ± 0.53, P = 0.073; 1.22 ± 0.07 vs. 1.19 ± 0.08, P = 0.627, respectively). Notably, neither chronic pain nor early recurrence, nor any other postoperative complications were observed in either group throughout the follow-up period, which extended for at least 6 months (range: 6-18 months). CONCLUSION: In the context of laparoscopic inguinoscrotal hernia repair, the incidence and volume of seroma can be significantly reduced through the implementation of internal orifice narrowing achieved by suturing the divided distal hernia sac. And, this reduction in seroma formation was not associated elevation in postoperative pain levels or recurrence rates.

'Passive' nanoparticles for organ-selective systemic delivery: design, mechanism and perspective.

Nanotechnology has shown tremendous success in the drug delivery field for more effective and safer therapy, and has recently enabled the clinical approval of RNA medicine, a new class of therapeutics. Various nanoparticle strategies have been developed to improve the systemic delivery of therapeutics, among which surface modification of targeting ligands on nanoparticles has been widely explored for 'active' delivery to a specific organ or diseased tissue. Meanwhile, compelling evidence has recently been reported that organ-selective targeting may also be achievable by systemic administration of nanoparticles without surface ligand modification. In this Review, we highlight this unique set of 'passive' nanoparticles and their compositions and mechanisms for organ-selective delivery. In particular, the lipid-based, polymer-based, and biomimetic nanoparticles with tropism to different specific organs after intravenous administration are summarized. The underlying mechanisms (e.g., protein corona and size effect) of these nanosystems for organ selectivity are also extensively discussed. We further provide perspectives on the opportunities and challenges in this exciting area of organ-selective systemic nanoparticle delivery.

ROS-Responsive Nanoparticle Delivery of mRNA and Photosensitizer for Combinatorial Cancer Therapy.

Messenger RNA (mRNA) therapy has shown tremendous potential for different diseases including cancer. While mRNA has been extensively used in cancer vaccine development as antigen or in cancer immunotherapy as immunomodulatory agent, the combination of mRNA therapy with photodynamic therapy has not been explored in cancer treatment. Herein, we report a reactive oxygen species (ROS)-responsive polymeric nanoparticle (NP) platform for first-in-field codelivery of mRNA and photosensitizer for effective cancer treatment. We developed ROS-responsive oligomer-based polymeric NPs and applied them to test a combination of p53 mRNA and indocyanine green (ICG). The ROS-triggered disassembly of the NPs could promote mRNA translation efficiency, whereby p53 expression induced apoptosis of lung tumor cells. Meanwhile, the released ICG could lead to generation of ROS under 808 nm laser irradiation to induce photodynamic therapy. The NP codelivery of p53 mRNA and ICG demonstrated an effective and safe anti-tumor effect in a lung cancer model.

Multistage Systemic and Cytosolic Protein Delivery for Effective Cancer Treatment.

Current clinical applications of protein therapy are largely limited to systemically accessible targets in vascular or extracellular areas. Major obstacles to the widespread application of protein therapeutics in cancer treatment include low membrane permeability and endosomal entrapment. Herein, we report a multistage nanoparticle (NP) strategy for systemic and cytosolic protein delivery to tumor cells, by encapsulating a protein conjugate, tetra-guanidinium (TG)-modified saporin, into tumor microenvironment (TME) pH-responsive polymeric NPs. Upon reaching the tumor site after systemic circulation, the polymeric NPs respond rapidly to the acidic tumor microenvironment and release the TG-saporin conjugates, which penetrate the tumor tissue and enter into tumor cells via TG-mediated cytosolic transportation. The TG-saproin NPs showed potent inhibition of lung cancer cell growth in vitro and in vivo. We expect that this multistage NP delivery strategy with long blood circulation, deep tumor penetration, and efficient cytosolic transport may be applicable to various therapeutic proteins for effective cancer treatment.

ODC (Ornithine Decarboxylase)-Dependent Putrescine Synthesis Maintains MerTK (MER Tyrosine-Protein Kinase) Expression to Drive Resolution.

OBJECTIVE: ODC (ornithine decarboxylase)-dependent putrescine synthesis promotes the successive clearance of apoptotic cells (ACs) by macrophages, contributing to inflammation resolution. However, it remains unknown whether ODC is required for other arms of the resolution program. Approach and Results: RNA sequencing of ODC-deficient macrophages exposed to ACs showed increases in mRNAs associated with heightened inflammation and decreases in mRNAs related to resolution and repair compared with WT (wild type) macrophages. In zymosan peritonitis, myeloid ODC deletion led to delayed clearance of neutrophils and a decrease in the proresolving cytokine, IL (interleukin)-10. Nanoparticle-mediated silencing of macrophage ODC in a model of atherosclerosis regression lowered IL-10 expression, decreased efferocytosis, enhanced necrotic core area, and reduced fibrous cap thickness. Mechanistically, ODC deletion lowered basal expression of MerTK (MER tyrosine-protein kinase)-an AC receptor-via a histone methylation-dependent transcriptional mechanism. Owing to lower basal MerTK, subsequent exposure to ACs resulted in lower MerTK-Erk (extracellular signal-regulated kinase) 1/2-dependent IL-10 production. Putrescine treatment of ODC-deficient macrophages restored the expression of both MerTK and AC-induced IL-10. CONCLUSIONS: These findings demonstrate that ODC-dependent putrescine synthesis in macrophages maintains a basal level of MerTK expression needed to optimally resolve inflammation upon subsequent AC exposure. Graphic Abstract: A graphic abstract is available for this article.

Intercalation-Driven Formation of siRNA Nanogels for Cancer Therapy.

RNA interference (RNAi) is a powerful approach in the treatment of various diseases including cancers. The clinical translation of small interfering RNA (siRNA)-based therapy requires safe and efficient delivery vehicles. Here, we report a siRNA nanogels (NG)-based delivery vehicle, which is driven directly by the intercalation between nucleic acid bis-intercalator and siRNA molecules. The intercalation-based siRNA NG exhibits good physiological stability and can enter cells efficiently via different endocytosis pathways. Furthermore, the siRNA NG can not only silence the target genes in vitro but also significantly inhibit the tumor growth in vivo. Therefore, this study provides an intercalation-based strategy for the development of a siRNA delivery platform for cancer therapy. To the best of our knowledge, this is the first report of the intercalation-driven siRNA NG.

Ultrasound-stimulated microbubbles contributes to radiotherapy in esophageal carcinoma.

This study aimed to explore the effect of ultrasound-stimulated microbubbles (USMBs) on tumor radiosensitivity in esophageal carcinoma (EC). The human EC cell line KYSE-510 and human umbilical vein endothelial cells (HUVECs) were exposed to radiation alone or in combination with USMBs. CCK-8, colony formation, and EdU assays were used to determine cell viability and proliferation. Cell apoptosis was assessed using flow cytometry. Cell migration and invasion were examined by wound healing and transwell assays. Western blotting showed that the protein levels were associated with apoptosis, epithelial-mesenchymal transition (EMT), and angiogenesis. An endothelial tube-forming assay was used to detect the angiogenic activity of HUVECs. Xenograft experiments were used to examine the effect of USMBs on EC radiosensitivity in vivo. The expression of Ki-67 in tumors was detected using immunohistochemistry. USMBs enhanced the suppressive effect of radiation on proliferation, migration, invasion, and EMT, and promoted radiation-induced apoptosis in EC cells in vitro. Angiogenesis in EC was suppressed by radiation and further inhibited by the combination of radiation and USMBs. In vivo experiments revealed that USMBs increased the radiosensitivity of ECs to tumor growth. Collectively, USMBs enhanced the effects of radiotherapy in esophageal carcinoma.

Feasibility, safety, and long-term efficacy of gastric peroral endoscopic myotomy (G-POEM) for postsurgical gastroparesis: a single-center and retrospective study of a prospective database.

BACKGROUND: Postsurgical gastroparesis is recognized as a gastrointestinal dysfunction syndrome following foregut surgery. Gastric peroral endoscopic myotomy (G-POEM) is suggested as a minimally invasive therapy for gastroparesis. But the long-term efficacy and safety of G-POEM in treating postsurgical gastroparesis are rarely explored. METHODS: The primary outcomes included the symptomatic improvement based on gastroparesis cardinal symptoms index (GCSI) and the improvement of gastric emptying. The secondary outcomes included the improvement of gastroesophageal reflux symptoms and complications of G-POEM. RESULTS: The severity of postsurgical gastroparesis was not associated with the onset time and the course of the disease. G-POEM significantly reduced GCSI throughout the follow-up period (p < 0.0001). For different anastomotic site, a significant improvement of GCSI was found at 6 month post-G-POEM (F4,165 = 74.18, p < 0.0001). Subscale analysis of GCSI showed that nausea/vomiting, post-prandial fullness/early satiety, and bloating were improved significantly at 6-month post-G-POEM (p < 0.0001, respectively). Half-emptying and whole-emptying time were significantly shortened in patients with different anastomotic site post-G-POEM (half-emptying time: F3,174 = 65.44, p < 0.0001; whole-emptying time: F3,174 = 54.85, p < 0.0001). The emptying of ioversol was obviously accelerated after G-POEM. GCSI wasn't related to pyloric length, pyloric diameter, and thickness of pyloric wall. GERDQ was also used to evaluate the clinical efficacy of G-POEM. For each time points, GERDQ didn't differ significantly in patients with different anastomotic site (F4,104 = 0.8075, p = 0.5231). For patients with different anastomotic site, GERDQ was improved significantly at different time points (F4,104 = 59.11, p < 0.0001). The higher the esophageal anastomotic site was, the faster G-POEM improved the symptoms of gastroesophageal reflux. No one required re-hospitalization for any complication. CONCLUSION: G-POEM is a minimally invasive therapy with long-term effectiveness and safety in treating postsurgical gastroparesis.

Sugar-Nanocapsules Imprinted with Microbial Molecular Patterns for mRNA Vaccination.

Innate immune cells recognize and respond to pathogen-associated molecular patterns. In particular, polysaccharides found in the microbial cell wall are potent activators of dendritic cells (DCs). Here, we report a new class of nanocapsules, termed sugar-capsules, entirely composed of polysaccharides derived from the microbial cell wall. We show that sugar-capsules with a flexible polysaccharide shell and a hollow core efficiently drain to lymph nodes and activate DCs. In particular, sugar-capsules composed of mannan (Mann-capsule) carrying mRNA (mRNA) promote strong DC activation, mRNA translation, and antigen presentation on DCs. Mann-capsules elicit robust antigen-specific CD4+ and CD8α+ T-cell responses with antitumor efficacy in vivo. The strategy presented in this study is generally applicable for utilizing pathogen-derived molecular patterns for vaccines and immunotherapies.

Dual Hypoxia-Targeting RNAi Nanomedicine for Precision Cancer Therapy.

As a hallmark of solid tumors, hypoxia promotes tumor growth, metastasis, and therapeutic resistance by regulating the expression of hypoxia-related genes. Hypoxia also represents a tumor-specific stimulus that has been exploited for the development of bioreductive prodrugs and advanced drug delivery systems. Cell division cycle 20 (CDC20) functions as an oncogene in tumorigenesis, and we demonstrated the significant upregulation of CDC20 mRNA in the tumor vs paratumor tissues of breast cancer patients and its positive correlation with tumor hypoxia. Herein, a hypoxia-responsive nanoparticle (HRNP) was developed by self-assembly of the 2-nitroimidazole-modified polypeptide and cationic lipid-like compound for delivery of siRNA to specifically target CDC20, a hypoxia-related protumorigenic gene, in breast cancer therapy. The delivery of siCDC20 by HRNPs sufficiently silenced the expression of CDC20 and exhibited potent antitumor efficacy. We expect that this strategy of targeting hypoxia-correlated protumorigenic genes by hypoxia-responsive RNAi nanoparticles may provide a promising approach in cancer therapy.

Oxidative-Species-Selective Materials for Diagnostic and Therapeutic Applications.

With the increasing recognition of the diverse roles and significance of oxidative species in the pathogenesis of many diseases, a tremendous amount of work on the development of oxidative-species-responsive materials has been conducted for 1) detecting oxygen metabolites or diagnosis of oxidative-stress-relevant diseases, 2) reducing oxidative stress in the disease sites, and/or 3) delivering therapeutic and diagnostic agents. In this review, we first discuss the distinct features and biological functions of each oxidative species. Then the selectivity and sensitivity of chemical linkers/groups to specific oxidative species and the underlying chemistry of their particular interactions are systematically elucidated. Their potential biomedical applications are also highlighted. We expect that this comprehensive review will provide more insights for the design and development of oxidative-species-selective materials for more effective diagnostic and therapeutic applications.

Structural Transformative Antioxidants for Dual-Responsive Anti-Inflammatory Delivery and Photoacoustic Inflammation Imaging.

We have synthesized a PEGylated, phenylboronic acid modified L-DOPA pro-antioxidant (pPAD) that can self-assemble into nanoparticles (pPADN) for the loading of a model glucocorticoid dexamethasone (Dex) through 1,3-diol/phenylboronic acid chemistry and hydrophobic interactions for more effective treatment of inflammation. Upon exposure to ROS, pPADN convert into the active form of L-DOPA, and a cascade of oxidative reactions transform it into antioxidative melanin-like materials. Concomitantly, the structural transformation of pPADN triggers the specific release of Dex, along with the acidic pH of inflammatory tissue. In a rat model of osteoarthritis, Dex-loaded pPADN markedly mitigate synovial inflammation, suppress joint destruction and cartilage matrix degradation, with negligible in vivo toxicity. Moreover, in situ structural transformation makes pPADN suitable for noninvasive monitoring of therapeutic effects as a photoacoustic imaging contrast agent.

An ultra-long circulating nanoparticle for reviving a highly selective BCR-ABL inhibitor in long-term effective and safe treatment of chronic myeloid leukemia.

Nanotechnology has demonstrated great promise for the development of more effective and safer cancer therapies. We recently developed a highly selective inhibitor of BCR-ABL fusion tyrosine kinase for chronic myeloid leukemia (CML). However, the poor drug-like properties were hurdles to its further clinical development. Herein, we re-investigate it by conjugating an amphiphilic polymer and self-assembling into a nanoparticle (NP) with a high loading (~10.3%). The formulation greatly improved its solubility and drastically extended its circulation half-life from ~5.3 to ~117 h (>20-fold). In the 150 days long-term engraftment model experiment, long intravenous dosing intervals of the NPs (every 4 or 8 days) exhibited much better survival and negligible toxicities as compared to daily oral administration of the inhibitor. Moreover, the NPs showed excellent inhibition of tumor growth in the subcutaneous xenograft model. All results suggest that the ultra-long circulating pro-drug NP may provide an effective and safe therapeutic strategy for BCR-ABL-positive CML.

Peptide-Based Autophagic Gene and Cisplatin Co-delivery Systems Enable Improved Chemotherapy Resistance.

Cisplatin-based chemotherapy is a widely used first-line strategy for numerous cancers. However, drug resistances are often inevitable accompanied by the long-term use of cisplatin in vivo, significantly hampering its therapeutic efficacy and clinical outcomes. Among others, autophagy induction is one of the most common causes of tumor resistance to cisplatin. Herein, a self-assembled nanoprodrug platform was developed with the synergistic effect of cisplatin and RNAi to fight against cisplatin-resistant lung cancer. The nanoprodrug platform consists of three molecular modules, including prodrug complex of Pt(IV)-peptide-bis(pyrene), DSPE-PEG, and cRGD-modified DSPE-PEG. The Pt(IV) is immobilized with peptide via amide bonds, allowing the Pt(IV) to be loaded with a loading efficiency of >95% and rapid-release active platinum ions (Pt(II)) in the presence of glutathione (GSH). Meanwhile, the peptide of the prodrug complex could efficiently deliver Beclin1 siRNA ( Beclin1 is an autophagy initiation factor) to the cytoplasm, thereby leading to autophagy inhibition. In addition, incorporation of DSPE-PEG and cRGD-modified DSPE-PEG molecules improves the biocompatibility and cellular uptake of the nanoprodrug platform. In vivo results also indicate that the nanoprodrug platform significantly inhibits the growth of a cisplatin-resistant tumor on xenograft mice models with a remarkable inhibition rate, up to 84% after intravenous injection.

Emerging Two-Dimensional Nanomaterials for Cancer Therapy.

Two-dimensional (2D) nanomaterials have drawn tremendous attention due to their unique physicochemical properties and promising applications in the fields of electronics, energy storage, and catalysis. Recently, the biomedicine community has gradually started to recognize the great potential of these nanostructured materials for biomedical applications - in particular those related to cancer therapy. In this review, we provide a brief overview of a few representative 2D nanomaterials, discuss their preparation strategies and physicochemical properties, and highlight their applications in cancer nanomedicine. We expect that this review will shed some light on the new opportunities associated with 2D nanomaterials for biomedical research.

Theranostic near-infrared fluorescent nanoplatform for imaging and systemic siRNA delivery to metastatic anaplastic thyroid cancer.

Anaplastic thyroid cancer (ATC), one of the most aggressive solid tumors, is characterized by rapid tumor growth and severe metastasis to other organs. Owing to the lack of effective treatment options, ATC has a mortality rate of ∼100% and median survival of less than 5 months. RNAi nanotechnology represents a promising strategy for cancer therapy through nanoparticle (NP) -mediated delivery of RNAi agents (e.g., siRNA) to solid tumors for specific silencing of target genes driving growth and/or metastasis. Nevertheless, the clinical success of RNAi cancer nanotherapies remains elusive in large part because of the suboptimal systemic siRNA NP delivery to tumors and the fact that tumor heterogeneity produces variable NP accumulation and thus, therapeutic response. To address these challenges, we here present an innovative theranostic NP platform composed of a near-infrared (NIR) fluorescent polymer for effective in vivo siRNA delivery to ATC tumors and simultaneous tracking of the tumor accumulation by noninvasive NIR imaging. The NIR polymeric NPs are small (∼50 nm), show long blood circulation and high tumor accumulation, and facilitate tumor imaging. Systemic siRNA delivery using these NPs efficiently silences the expression of V-Raf murine sarcoma viral oncogene homolog B (BRAF) in tumor tissues and significantly suppresses tumor growth and metastasis in an orthotopic mouse model of ATC. These results suggest that this theranostic NP system could become an effective tool for NIR imaging-guided siRNA delivery for personalized treatment of advanced malignancies.

Glutathione-Scavenging Poly(disulfide amide) Nanoparticles for the Effective Delivery of Pt(IV) Prodrugs and Reversal of Cisplatin Resistance.

Despite the broad antitumor spectrum of cisplatin, its therapeutic efficacy in cancer treatment is compromised by the development of drug resistance in tumor cells and systemic side effects. A close correlation has been drawn between cisplatin resistance in tumor cells and increased levels of intracellular thiol-containing species, especially glutathione (GSH). The construction of a unique nanoparticle (NP) platform composed of poly(disulfide amide) polymers with a high disulfide density for the effective delivery of Pt(IV) prodrugs capable of reversing cisplatin resistance through the disulfide-group-based GSH-scavenging process, as described herein, is a promising route by which to overcome limitations associated with tumor resistance. Following systematic screening, the optimized NPs (referred to as CP5 NPs) showed a small particle size (76.2 nm), high loading of Pt(IV) prodrugs (15.50% Pt), a sharp response to GSH, the rapid release of platinum (Pt) ions, and notable apoptosis of cisplatin-resistant A2780cis cells. CP5 NPs also exhibited long blood circulation and high tumor accumulation after intravenous injection. Moreover, in vivo efficacy and safety results showed that CP5 NPs effectively inhibited the growth of cisplatin-resistant xenograft tumors with an inhibition rate of 83.32% while alleviating serious side effects associated with cisplatin. The GSH-scavenging nanoplatform is therefore a promising route by which to enhance the therapeutic index of Pt drugs used currently in cancer treatment.