Mitochondria targeted drug delivery system overcoming drug resistance in intrahepatic cholangiocarcinoma by reprogramming lipid metabolism.

The challenge of drug resistance in intrahepatic cholangiocarcinoma (ICC) is intricately linked with lipid metabolism reprogramming. The hepatic lipase (HL) and the membrane receptor CD36 are overexpressed in BGJ398-resistant ICC cells, while they are essential for lipid uptake, further enhancing lipid utilization in ICC. Herein, a metal-organic framework-based drug delivery system (OB@D-pMOF/CaP-AC, DDS), has been developed. The specifically designed DDS exhibits a successive targeting property, enabling it to precisely target ICC cells and their mitochondria. By specifically targeting the mitochondria, DDS produces reactive oxygen species (ROS) through its sonodynamic therapy effect, achieving a more potent reduction in ATP levels compared to non-targeted approaches, through the impairment of mitochondrial function. Additionally, the DDS strategically minimizes lipid uptake through the incorporation of the anti-HL drug, Orlistat, and anti-CD36 monoclonal antibody, reducing lipid-derived energy production. This dual-action strategy on both mitochondria and lipids can hinder energy utilization to restore drug sensitivity to BGJ398 in ICC. Moreover, an orthotopic mice model of drug-resistant ICC was developed, which serves as an exacting platform for evaluating the multifunction of designed DDS. Upon in vivo experiments with this model, the DDS demonstrated exceptional capabilities in suppressing tumor growth, reprogramming lipid metabolism and improving immune response, thereby overcoming drug resistance. These findings underscore the mitochondria-targeted DDS as a promising and innovative solution in ICC drug resistance.

Thermosensitive gel-nano system against esophageal cancer via restoring p53 activity and boosting T-cell immunity.

In esophageal cancer (EC), clinical specimen testing has uncovered a significant increase in BTB and CNC homolog 1 (BACH1) expression and a shift towards an immunosuppressive environment, alongside a notable decrease in p53 protein expression. Therefore, therapeutic strategies focusing on BACH1 inhibition and p53 upregulation appear promising. Traditional oral treatments for EC lack precision and efficacy. Here, we propose a novel approach employing tumor-targeted nanoparticles (NPs) for drug delivery. However, the formation of a drug reservoir at the esophageal site, crucial for the sustained release of therapeutics, presents significant challenges in nano-delivery systems for EC treatment. To address this, we developed a thermosensitive hydrogel composed of F127 and tannic acid, serving as a vehicle for NP loading. These NPs, synthesized through the emulsion/volatization methods of mPEG-PLGA-PLL-cRGD, facilitate in situ drug delivery. Upon contacting esophageal tissue, the hydrogel transitions to a gel, adhering to the lining and enabling sustained release of encapsulated therapeutics. The formulation encompasses NPs laden with small interfering RNA targeting BACH1 (siBACH1) and the p53 activator PRIMA-1, creating a cohesive gel-nano system. Preliminary biological assessments demonstrate that this injectable, thermosensitive gel-nano system adheres effectively to esophageal tissue and targets EC cells. For better modeling clinical outcomes, a patient-derived organoid xenograft (PDOX) model was innovated, involving transplantation of EC-derived organoids into humanized mice, reconstructed with peripheral blood mononuclear cells (PBMCs). Post-treatment analysis showed substantial EC growth inhibition (89.51% tumor inhibition rate), significant BACH1 level reduction, restored anti-tumor immune responses, and pronounced tumor apoptosis. In summary, our study introduces a thermosensitive gel-nano system for EC treatment via restoring p53 activity and boosting T-cell immunity, with potential for clinical application.

Application of Dynamic Contrast-Enhanced Ultrasound in Evaluation the Activity of Crohn's Disease.

BACKGROUND AND OBJECTIVE: The dynamic assessment of disease activity during the follow-up of patients with Crohn's disease (CD) remains a significant challenge. In this study, we aimed to identify the role of dynamic contrast-enhanced ultrasound (DCE-US) in the evaluation of activity of CD. METHODS: In the retrospective study, patients diagnosed with CD in our hospital were included. All the diagnoses were confirmed by clinical symptoms and ileocolonoscopical results. All patients underwent intestinal ultrasound and contrast-enhanced ultrasound (CEUS) examinations within 1 week of the ileocolonoscopy examinations. Acuson Sequoia (Siemens Healthineers, Mountain View, CA, USA) and Resona R9 Elite (Mindray Medical Systems, China) with curved array and Line array transducers were used. The CEUS examination was performed with SonoVue (Bracco SpA, Milan, Italy). DCE-US analysis was performed by UltraOffice (version: 0.3-2010, Mindray Medical Systems, China) software. Two regions of interest (ROIs) were set in the anterior section of the infected bowel wall and its surrounding normal bowel wall 2 cm distant from the inflamed area. Time-intensity curves (TICs) were generated and quantitative perfusion parameters were obtained after curve fittings. The Simple Endoscopic Score for Crohn's disease (SES-CD) was regarded as the reference standard to evaluate the activity of CD. The receiver operating characteristic curve (ROC) analyses were used to determine the diagnostic efficiency of DCE-US quantitative parameters. RESULTS: From March 2023 to November 2023, 52 CD patients were included. According to SES-CD score, all patients were divided into active group with the SES-CD score > 5 (n = 39) and inactive group SES-CD score < 5 (n = 13). Most of the active CD patients showed bowel wall thickness (BWT) > 4.2 mm (97.4%, 38/39) or mesenteric fat hypertrophy (MFH) on intestinal ultrasound (US) scan (69.2%, 27/39). Color Doppler signal of the bowel wall mostly showed spotty or short striped blood flow signal in active CD patients (56.4%, 22/39). According to CEUS enhancement patterns, most active CD patients showed a complete hyperenhancement of the entire intestinal wall (61.5%, 24/39). The TICs of active CD showed an earlier enhancement, higher peak intensity, and faster decline. Among all CEUS quantitative parameters, amplitude-derived parameters peak enhancement (PE), wash-in area under the curve (WiAUC), wash-in rate (WiR), wash-in perfusion index (WiPI), and wash-out rate (WoR) were significantly higher in active CD than in inactive CD (p < 0.05). The combined AUROC of intestinal ultrasound features and DCE-US quantitative perfusion parameters in the diagnosis of active CD was 0.987, with 97.4% sensitivity, 100% specificity, and 98.1% accuracy. CONCLUSIONS: DCE-US with quantitative perfusion parameters is a potential useful noninvasive imaging method to evaluate the activity of Crohn's disease.

Nanosystem Delivers Senescence Activators and Immunomodulators to Combat Liver Cancer.

CD47 blockade has emerged as a promising immunotherapy against liver cancer. However, the optimization of its antitumor effectiveness using efficient drug delivery systems or combinations of therapeutic agents remains largely incomplete. Here, patients with liver cancer co-expressing CD47 and CDC7 (cell division cycle 7, a negative senescence-related gene) are found to have the worst prognosis. Moreover, CD47 is highly expressed, and senescence is inhibited after the development of chemoresistance, suggesting that combination therapy targeting CD47 and CDC7 to inhibit CD47 and induce senescence may be a promising strategy for liver cancer. The efficacy of intravenously administered CDC7 and CD47 inhibitors is limited by low uptake and short circulation times. Here, inhibitors are coloaded into a dual-targeted nanosystem. The sequential release of the inhibitors from the nanosystem under acidic conditions first induces cellular senescence and then promotes immune responses. In an in situ liver cancer mouse model and a chemotherapy-resistant mouse model, the nanosystem effectively inhibited tumor growth by 90.33% and 85.15%, respectively. Overall, the nanosystem in this work achieved the sequential release of CDC7 and CD47 inhibitors in situ to trigger senescence and induce immunotherapy, effectively combating liver cancer and overcoming chemoresistance.

Long-acting anti-inflammatory injectable DEX-Gel with sustained release and self-healing properties regulates TH1/TH2 immune balance for minimally invasive treatment of allergic rhinitis.

BACKGROUND: Allergic rhinitis (AR) is a prevalent immune-related allergic disease, and corticosteroid nasal sprays serve as the primary treatment for this patient population. However, their short duration of efficacy and frequent administration pose challenges, leading to drug wastage and potential adverse effects. To overcome these limitations, we devised a novel approach to formulate DEX-Gel by incorporating dexamethasone (DEX) into a blend of Pluronic F127, stearic acid (SA), and polyethylene glycol 400 (PEG400) to achieve sustained-release treatment for AR. RESULTS: Following endoscopic injection into the nasal mucosa of AR rats, DEX-Gel exhibited sustained release over a 14-day period. In vivo trials employing various assays, such as flow cytometry (FC), demonstrated that DEX-Gel not only effectively managed allergic symptoms but also significantly downregulated helper T-cells (TH) 2 and TH2-type inflammatory cytokines (e.g., interleukins 4, 5, and 13). Additionally, the TH1/TH2 cell ratio was increased. CONCLUSION: This innovative long-acting anti-inflammatory sustained-release therapy addresses the TH1/TH2 immune imbalance, offering a promising and valuable approach for the treatment of AR and other inflammatory nasal diseases.

Dissolving microneedles-based programmed delivery system for enhanced chemo-immunotherapy of melanoma.

Immune checkpoint blockade, especially the programmed cell death ligand 1 (PD-L1) blockade, has revolutionized the treatment of melanoma. However, PD-1/PD-L1 monotherapy leads to unsatisfactory therapeutic outcomes. The immunotherapy of melanoma could be improved by adding doxorubicin (DOX), which triggers immunogenic cell death (ICD) effect to activate anti-tumor immunity. Additionally, microneedles, especially dissolving microneedles (dMNs), can further enhance outcomes of chemo-immunotherapy due to the physical adjuvant effect of dMNs. Herein, we developed the dMNs-based programmed delivery system that incorporated pH-sensitive and melanoma-targeting liposomes to co-deliver DOX and siPD-L1, achieving enhanced chemo-immunotherapy of melanoma (si/DOX@LRGD dMNs). The incorporated si/DOX@LRGD LPs demonstrated uniform particle size, pH-sensitive drug release, high in vitro cytotoxicity and targeting ability. Besides, si/DOX@LRGD LPs effectively downregulated the expression of PD-L1, induced tumor cell apoptosis and triggered ICD effect. The si/DOX@LRGD LPs also showed deep penetration (approximately 80 µm) in 3D tumor spheroids. Moreover, si/DOX@LRGD dMNs dissolved rapidly into the skin and had sufficient mechanical strength to penetrate skin, reaching a depth of approximately 260 µm in mice skin. In mice model of melanoma tumor, si/DOX@LRGD dMNs exhibited better anti-tumor efficacy than monotherapy by dMNs and tail intravenous injection at the same dose. This was due to the higher cytotoxic CD8+ T cells and the secreted cytotoxic cytokine IFN-γ evoked by si/DOX@LRGD dMNs, thereby eliciting strong T-cell mediated immune response and resulted in enhanced anti-tumor effects. In conclusion, these findings suggested that si/DOX@LRGD dMNs provided a promising and effective strategy for enhanced chemo-immunotherapy of melanoma.

Nano Ultrasound Contrast Agent for Synergistic Chemo-photothermal Therapy and Enhanced Immunotherapy Against Liver Cancer and Metastasis.

Advanced liver cancer is the most fatal malignant cancer, and the clinical outcomes of treatment are not very satisfactory due to the complexity and heterogeneity of the tumor. Combination therapy can efficiently enhance tumor treatment by stimulating multiple pathways and regulating the tumor immune microenvironment. Nanodrug delivery systems have become attractive candidates for combined strategies for liver cancer treatment. This study reports a nano ultrasound contrast agent (arsenic trioxide (ATO)/PFH NPs@Au-cRGD) to integrate diagnosis and treatment for efficient ultrasound imaging and liver cancer therapy. This nanodrug delivery system promotes tumor-associated antigens release through ATO-induced ferroptosis and photothermal-induced immunogenic cell death, enhancing the synergistic effects of ATO and photothermal therapy in human Huh7 and mouse Hepa1-6 cells. This drug delivery system successfully activates the antitumor immune response and promotes macrophage M1 polarization in tumor microenvironment with low side effects in subcutaneous and orthotopic liver cancer. Furthermore, tumor metastasis is inhibited and long-term immunological memory is also established in orthotopic liver cancer when the nanodrug delivery system is combined with anti-programmed death-ligand 1 (PD-L1) immunotherapy. This safe nanodrug delivery system can enhance antitumor therapy, inhibit lung metastasis, and achieve visual assessment of therapeutic efficacy, providing substantial potential in clinic applications for liver cancer.

Gut microbial metabolite butyrate improves anticancer therapy by regulating intracellular calcium homeostasis.

BACKGROUND AND AIMS: Gut microbiota are recognized to be important for anticancer therapy, yet the underlying mechanism is not clear. Here, through the analysis of clinical samples, we identify the mechanism by which the gut microbial metabolite butyrate inhibits HCC and then explore new strategies for HCC treatment. APPROACH AND RESULTS: In our study, we demonstrate that gut microbial metabolite butyrate improves anticancer therapy efficacy by regulating intracellular calcium homeostasis. Using liquid chromatography-mass spectrometry analysis, we found that butyrate metabolism is activated in HCC patients compared with healthy individuals. Butyrate levels are lower in the plasma of HCC patients by gas chromatography-mass spectrometry (GC-MS) analysis. Butyrate supplementation or depletion of short-chain Acyl-CoA dehydrogenase (SCAD) gene (ACADS), encoding a key enzyme for butyrate metabolism, significantly inhibits HCC proliferation and metastasis. The profiling analysis of genes upregulated by butyrate supplementation or ACADS knockdown reveals that calcium signaling pathway is activated, leading to dysregulation of intracellular calcium homeostasis and production of reactive oxygen species. Butyrate supplementation improves the therapy efficacy of a tyrosine kinase inhibitor sorafenib. On the basis of these findings, we developed butyrate and sorafenib coencapsulated mPEG-PLGA-PLL nanoparticles coated with anti-GPC3 antibody (BS@PEAL-GPC3) to prolong the retention time of drugs and enhance drug targeting, leading to high anticancer efficacy. BS@PEAL-GPC3 nanoparticles significantly reduce HCC progression. In addition, BS@PEAL-GPC3 nanoparticles display excellent HCC targeting with excellent safety. CONCLUSIONS: In conclusion, our findings provide new insight into the mechanism by which the gut microbial metabolites inhibit HCC progression, suggesting a translatable therapeutics approach to enhance the clinical targeted therapeutic efficacy.

Inhibition of atherosclerosis progression by modular micelles.

Atherosclerosis is a chronic disease initiated by lipid-mediated vascular inflammation. From the perspective of conventional treatment, it is difficult to achieve good therapeutic effects via regulation of a single lipid or anti-inflammatory effects. Herein, we designed an amphiphilic low molecular weight heparin-unsaturated fatty acid conjugate (LMWH-uFA) that acted as both an antiatherosclerotic agent and a nanocarrier with self-delivery properties. Structurally, LMWH-uFA self-assembled to form micelles with LMWH as the shell and uFA as the core, without any additives, which guaranteed their biosafety. Functionally, the hydrophilic segment, LMWH, prevented monocyte adhesion to inhibit early vascular inflammation, and the hydrophobic segment, uFA, could participate in the regulation of blood lipids. The anti-inflammatory drug rapamycin (RAP) was encapsulated in the micellar core, which improved its water solubility, and cooperated with LMWH to achieve targeted blockade of the vascular inflammation cascade at P-selectin. The three treatment modules, LMWH, uFA and RAP, were integrated into one system for different therapeutic targets in anticipation of better efficacy. In an atherosclerosis mouse model, RAP-loaded NPs significantly reduced the plaque area and showed satisfactory curative effects, which were related to the targeting of lipid regulation and inflammation. Thus, these modular micellar nanoparticles offer a promising approach for the clinical treatment of atherosclerosis.

Deposition of hydrophilic Ti3C2Tx on a superhydrophobic ZnO nanorod array for improved surface-enhanced raman scattering performance.

BACKGROUND: Superhydrophobic substrate modifications are an effective way to improve SERS sensitivity by concentrating analyte molecules into a small surface area. However, it is difficult to manipulate low-volume liquid droplets on superhydrophobic substrates. RESULTS: To overcome this limitation, we deposited a hydrophilic Ti3C2Tx film on a superhydrophobic ZnO nanorod array to create a SERS substrate with improved analyte affinity. Combined with its interfacial charge transfer properties, this enabled a rhodamine 6G detection limit of 10-11 M to be achieved. In addition, the new SERS substrate showed potential for detection of biological macromolecules, such as microRNA. CONCLUSION: Combined with its facile preparation, the SERS activity of ZnO/Ti3C2Tx suggests it may provide an ultrasensitive environmental pollutant-monitoring and effective substrate for biological analyte detection.

Overcoming AZD9291 Resistance and Metastasis of NSCLC via Ferroptosis and Multitarget Interference by Nanocatalytic Sensitizer Plus AHP-DRI-12.

The acquired resistance to Osimertinib (AZD9291) greatly limits the clinical benefit of patients with non-small cell lung cancer (NSCLC), whereas AZD9291-resistant NSCLCs are prone to metastasis. It's challenging to overcome AZD9291 resistance and suppress metastasis of NSCLC simultaneously. Here, a nanocatalytic sensitizer (VF/S/A@CaP) is proposed to deliver Vitamin c (Vc)-Fe(II), si-OTUB2, ASO-MALAT1, resulting in efficient inhibition of tumor growth and metastasis of NSCLC by synergizing with AHP-DRI-12, an anti-hematogenous metastasis inhibitor by blocking the amyloid precursor protein (APP)/death receptor 6 (DR6) interaction designed by our lab. Fe2+ released from Vc-Fe(II) generates cytotoxic hydroxyl radicals (•OH) through Fenton reaction. Subsequently, glutathione peroxidase 4 (GPX4) is consumed to sensitize AZD9291-resistant NSCLCs with high mesenchymal state to ferroptosis due to the glutathione (GSH) depletion caused by Vc/dehydroascorbic acid (DHA) conversion. By screening NSCLC patients' samples, metastasis-related targets (OTUB2, LncRNA MALAT1) are confirmed. Accordingly, the dual-target knockdown plus AHP-DRI-12 significantly suppresses the metastasis of AZD9291-resistant NSCLC. Such modality leads to 91.39% tumor inhibition rate in patient-derived xenograft (PDX) models. Collectively, this study highlights the vulnerability to ferroptosis of AZD9291-resistant tumors and confirms the potential of this nanocatalytic-medicine-based modality to overcome critical AZD9291 resistance and inhibit metastasis of NSCLC simultaneously.

Rapamycin-encapsulated costimulatory ICOS/CD40L-bispecific nanoparticles restrict pathogenic helper T-B-cell interactions while in situ suppressing mTOR for lupus treatment.

Excessive CD4+ T helper (Th)-B-cell interactions and loss of Treg homeostasis are crucial to the pathogenesis of systemic lupus erythematosus (SLE). Targeting the SLE-specific upregulated costimulatory molecules ICOS or CD40L on Th can block Th-B reciprocal activation, but single costimulatory molecular blockade exhibited unsatisfactory therapeutic efficacy due to pathway redundancy. As ICOS and CD40L nonredundantly and cooperatively promote Th-B-cell reciprocal activation, simultaneously blocking ICOS and CD40L may achieve a synergistic effect. Moreover, inhibition of overactivated mTOR signaling by rapamycin (RAP) can promote Treg expansion while restraining autoreactive T-B-cell activation, which can work as an adjuvant to pair with costimulation blockade to restore immune homeostasis. However, systemic administration of multiple immune modulators is hindered by limited drug enrichment at the target site and increased systemic toxicity. Here, we rationally designed RAP-encapsulated ICOS/CD40L bispecific nanoparticles (NPs) to achieve multitarget therapy in a disease-specific manner. Through ex vivo cocultures of Th and B cells from SLE mice or patients and in vivo SLE mouse models, we demonstrated that RAP-encapsulated ICOS/CD40L bispecific NPs selectively target SLE Th cells and potently inhibit Th-B-cell reciprocal activation by targeting dual costimulatory pathways. In addition, the sustained release of RAP benefits from the precise targeting ability of bispecific NPs to further inhibit in situ Th-B cells while promote bystander Treg cells, which help to significantly alleviate SLE progression in both inducible and spontaneous lupus models with no obvious toxicity.

Systemic Delivery of mPEG-Masked Trispecific T-Cell Nanoengagers in Synergy with STING Agonists Overcomes Immunotherapy Resistance in TNBC and Generates a Vaccination Effect.

T-cell engagers (TCEs) represent a breakthrough in hematological malignancy treatment but are vulnerable to antigen escape and lack a vaccination effect. The "immunologically cold" solid tumor presents substantial challenges due to intratumor heterogeneity and an immunosuppressive tumor microenvironment (TME). Here, a methoxy poly(ethylene glycol) (mPEG)-masked CD44×PD-L1/CD3 trispecific T-cell nanoengager loaded with the STING agonist c-di-AMP (CDA) (PmTriTNE@CDA) for the treatment of triple-negative breast cancer (TNBC) is rationally designed. PmTriTNE@CDA shows tumor-specific accumulation and is preferentially unmasked in response to a weakly acidic TME to prevent on-target off-tumor toxicity. The unmasked CD44×PD-L1/CD3 trispecific T-cell nanoengager (TriTNE) targets dual tumor-associated antigens (TAAs) to redirect CD8+ T cells for heterogeneous TNBC lysis while achieving PD-L1 blockade. PmTriTNE synergized with CDA to transform the cold tumor into a hot tumor, eradicate the large established TNBC tumor, and induce protective immune memory in a 4T1 orthotopic tumor model without causing obvious toxicity. PmTriTNE@CDA shows potent efficacy in cell line-derived xenograft (CDX) and patient-derived xenograft (PDX) mouse models. This study serves as a proof-of-concept demonstration of a nanobased TCEs strategy to expand therapeutic combinations that previously could not be achieved due to systemic toxicity with the aim of overcoming TNBC heterogeneity and immunotherapy resistance.

Programmed prodrug breaking the feedback regulation of P-selectin in plaque inflammation for atherosclerotic therapy.

Inflammation is the main driver of the aggravation of arteriosclerosis, and the complex inflammatory response in plaque is usually the result of the interaction of various cells and cytokines. Therefore, it is difficult to comprehensively regulate the inflammatory process of arteriosclerosis by intervening a single target, resulting in the poor effect of existing treatment method. Based on our clinical findings that P-selectin stably and highly expressed in patients' plaque endothelial cells, the programmed prodrug, low molecular weight heparin-indomethacin nanoparticles (LI NPs), were established as anti-inflammatory agent to multiphase inhibit arteriosclerosis by cascade interference of P-selectin. Structurally, LI NPs was obtained by simple esterification of low molecular weight heparin and indomethacin without any additives, guaranteeing the biocompatibility and applicability of LI NPs. Functionally, LI NPs could interfere with P-selectin in the inflammatory process, such as inhibiting macrophage adhesion, reducing the secretion of inflammatory factors, and inducing macrophage apoptosis. In the arteriosclerosis mice model, LI NPs significantly reduced the plaque area and showed satisfactory curative effect, which is related to the intervention of the multiphase inflammation between endothelial cells and macrophages. In conclusion, the programmed prodrug LI NPs offered a promising approach for the clinical therapy of arteriosclerosis.

Engineered PD-1/TIGIT dual-activating cell-membrane nanoparticles with dexamethasone act synergistically to shape the effector T cell/Treg balance and alleviate systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a potentially life-threatening autoimmune disease that is characterized by alterations in the balance between effector and regulatory CD4+ T cells. We observed the upregulation of the immune checkpoints (ICs) PD-1 and TIGIT in pathogenic CD4+ T cells during disease progression, and downregulation of their ligands PD-L1 and CD155. Inspired by biomimetic nanotechnology, we fabricated dexamethasone (DXM)-loaded IFN-γ-treated MHC class I deficient cancer membrane-coated nanoparticles (IM-MNPs/DXM) to safely harness the immunosuppressive power of tumor cells for the treatment of SLE. The IM-MNPs inherited the membrane functions, which allowed these particles to evade immune clearance and accumulate in inflammatory organs. The IM-MNPs specifically targeted SLE CD4+ T cells and agonist PD-1/TIGIT signaling to inhibit effector T cell function while enhancing the immunosuppressive function of regulatory T cells (Tregs). The sustained release of DXM inhibited the production of proinflammatory cytokines in the inflammatory microenvironment to further promote Treg-mediated immune homeostasis. The IM-MNPs/DXM showed significant therapeutic efficacy in ameliorating lupus nephritis (LN) and decreasing side effects in vivo. Therefore, the particle represents a promising platform to improve current SLE treatment efficacy while minimizing systemic side effects of DXM and ICs agonist therapy.

Nano-ultrasonic Contrast Agent for Chemoimmunotherapy of Breast Cancer by Immune Metabolism Reprogramming and Tumor Autophagy.

The functional status of innate immune cells is a considerable determinant of effective antitumor immune response. However, the triple-negative breast cancer tumor microenvironment with high lactic acid metabolism and high antioxidant levels limits immune cell survival, differentiation, and function. Here, we determine that the tumor microenvironment-responsive nano-ultrasonic contrast agent Pt(IV)/CQ/PFH NPs-DPPA-1 boosts the ratio of mature dendritic cells (mDCs) and proinflammatory macrophages by reprogramming the metabolism of immature DCs (iDCs) and tumor-associated macrophages (TAMs). Specifically, platinum(IV) in cancer cells or iDCs was reduced to cisplatin, which can increase the intracellular content of ROS and therefore enhance the ratio of mDCs and apoptotic tumor cells. Meanwhile, chloroquine (CQ) released from nanoparticles (NPs) minimizes protective autophagy caused by cisplatin in tumor cells and reprograms the metabolism of TAMs to enhance the proportion of proinflammatory macrophages, achieving a superior synergistic effect of chemoimmunotherapy combined with Pt(IV) and anti-PD-L1 peptide (DPPA-1). Furthermore, perfluorohexane (PFH) in NPs realizes monitoring treatment corresponding to ultrasound. Collectively, the nano-ultrasonic contrast agent supports a candidate for monitoring treatment and augmenting antitumor chemoimmunotherapy by suppressing tumor cell autophagy and reprogramming immunocyte metabolism.

ROS-responsive dexamethasone micelles normalize the tumor microenvironment enhancing hypericin in cancer photodynamic therapy.

The efficacy of photodynamic therapy (PDT) for cancer is limited owing to the abnormality of the tumor microenvironment (TME), such as the dysfunctional tumor vascular system leading to restricted drug distribution in tumor lesions, and hypoxia resulting in hampering the application of the photosensitizer because of the shortage of oxygen. Therefore, normalizing the TME is a novel strategy for enhancing the therapeutic efficacy of PDT. Herein, we designed and fabricated reactive oxygen species (ROS)-responsive micelles with a self-circulating release manner to co-deliver a glucocorticoid steroid dexamethasone (DXM) and a photosensitizer hypericin (HYP) (denoted as HDTM). The current drug delivery system showed the following advantageous properties: (1) The DXM inhibited the migration, invasion and angiogenesis of vein endothelial cells by suppressing the function of vascular endothelial growth factor, thus promoting the delivery of oxygen and HDTM into the tumor site. (2) When the HDTM arrived at the tumor site, the endogenous ROS partially cleaved the outer shell of the micelle to release the HYP and DXM. With the use of an external light source with a wavelength of 590 nm, the in situ released HYP was excited, enabling ROS production, which resulted in effective cell apoptosis. Moreover, the upregulated ROS further cleaved the micelles, thus achieving the subsequent self-circulating burst release of HYP and DXM for PDT. Notably, real-time accumulation and elimination of drugs can be monitored owing to the red fluorescence property of HYP. This facile design not only provides a platform for cancer theranostics, but also offers a feasible strategy to combat cancer in an integral way.

Exosome-liposome hybrid nanoparticle codelivery of TP and miR497 conspicuously overcomes chemoresistant ovarian cancer.

BACKGROUND: Although cisplatin-based chemotherapy has been used as the first-line treatment for ovarian cancer (OC), tumor cells develop resistance to cisplatin during treatment, causing poor prognosis in OC patients. Studies have demonstrated that overactivation of the phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) pathway is involved in tumor chemoresistance and that overexpression of microRNA-497 (miR497) may overcome OC chemotherapy resistance by inhibiting the mTOR pathway. However, the low transcriptional efficiency and unstable chemical properties of miR497 limit its clinical application. Additionally, triptolide (TP) was confirmed to possess a superior killing effect on cisplatin-resistant cell lines, partially through inhibiting the mTOR pathway. Even so, the clinical applications of TP are restricted by serious systemic toxicity and weak water solubility. RESULTS: Herein, whether the combined application of miR497 and TP could further overcome OC chemoresistance by synergically suppressing the mTOR signaling pathway was investigated. Bioinspired hybrid nanoparticles formed by the fusion of CD47-expressing tumor exosomes and cRGD-modified liposomes (miR497/TP-HENPs) were prepared to codeliver miR497 and TP. In vitro results indicated that the nanoparticles were efficiently taken up by tumor cells, thus significantly enhancing tumor cell apoptosis. Similarly, the hybrid nanoparticles were effectively enriched in the tumor areas and exerted significant anticancer activity without any negative effects in vivo. Mechanistically, they promoted dephosphorylation of the overactivated PI3K/AKT/mTOR signaling pathway, boosted reactive oxygen species (ROS) generation and upregulated the polarization of macrophages from M2 to M1 macrophages. CONCLUSION: Overall, our findings may provide a translational strategy to overcome cisplatin-resistant OC and offer a potential solution for the treatment of other cisplatin-resistant tumors.

CDCP1-targeted nanoparticles encapsulating phase-shift perfluorohexan for molecular US imaging in vitro.

BACKGROUND: Molecular targeted contrast-enhanced ultrasound (CEUS) imaging is a potential imaging strategy to improve the diagnostic accuracy of conventional ultrasound (US) imaging. US contrast agents are usually micrometer-sized and non-target gas bubbles while nano-sized and targeted agents containing phase-shift materials absorb more attractions for their size and the liquid core and excellent molecular imaging effect. METHODS: PLGA12k-mPEG2k-NH2, DSPE-mPEG2k and perfluorohexan (PFH) were used to construct a new targeted ultrasound contrast agent with CUB domain-containing protein 1 (CDCP1) receptor for the detection and diagnosis of prostate cancer. The potential of tumor-targeted nanoparticles (CDCP1-targeted perfluorohexan-loaded phase-transitional nanoparticles, anti-CDCP1 NPs) as contrast agents for ultrasound (US) imaging was assessed in vitro. Moreover, studies on the cytotoxicity and the targeting ability of anti-CDCP1 NPs assisted by US were carried out. RESULTS: The results showed that anti-CDCP1 NPs had low cytotoxicity, and with the increasing of polymer concentration in anti-CDCP1 NPs, the CEUS imaging of agent gradually enhanced, and enhanced imaging associated with the length of observing time. Furthermore, it was testified that anti-CDCP1 assisted the agent to target cells expressing CDCP1, which demonstrated the active targeting of anti-CDCP1 NPs in vitro. CONCLUSION: All in all, the feasibility of using targeted anti-CDCP1 NPs to enhance ultrasound imaging has been demonstrated in vitro, which laid a solid foundation for molecular US imaging in vivo, and anti-CDCP1 NPs might have a great clinical application prospect.