Microfluidized Dextran Microgels Loaded with Cisplatin/SPION Lipid Nanotherapeutics for Local Colon Cancer Treatment via Oral Administration.

Multifunctional sequential targeted delivery system is developed as an efficient therapeutic strategy against malignant tumors with selective accumulation and minimal systemic drug absorption. The therapeutic system is comprised of microfluidized dextran microgels encapsulating cisplatin/superparamagnetic iron oxide nanoparticles (SPIONs)-loaded trilaurin-based lipid nanoparticles (LNPs). The microgel system is imparted hierarchically dual targeting via dextran and folic acid (FA) residues, leading to increases both in retention of the microgels in colon and in cellular uptake of the therapeutic LNPs by colon cancer cells while being used for oral therapeutic delivery. Encapsulation of the therapeutic LNPs into dextran microgels attained by microfluidized crosslinking reaction reduces gastrointestinal adhesion and prevents the FA-modified LNPs from cellular transport by proton-coupled FA transporters in small intestine during their oral delivery to colon. Upon enzymatic degradation of the dextran microgels by dextranase present exclusively in colon, LNPs thus released become more recognizable and readily internalized by FA receptor-overexpressing colon cancer cells. The combined chemo/magnetothermal therapeutic effect of dual targeted lipid nanoparticle-loaded microgels from entrapped lipidized cisplatin and alternating magnetic field-treated SPIONs significantly inhibits tumor growth and suppresses metastatic peritoneal carcinomatosis in orthotopic colon cancer-bearing mice.

Photothermal/NO combination therapy from plasmonic hybrid nanotherapeutics against breast cancer.

In this study, a plasmon-semiconductor nanotheranostic system comprising Au nanostars/graphene quantum dots (AuS/QD) hybrid nanoparticles loaded with BNN6 and surface modified with PEG-pyrene was developed for the photo-triggered hyperthermia effect and NO production as the dual modality treatment against orthotopic triple-negative breast cancer. The structure and morphology of the hybrid nanodevice was characterized and the NIR-II induced thermal response and NO production was determined. The hybrid nanodevice has shown enhanced plasmonic energy transfer from localized surface plasmonic resonance of Au nanostars to QD semiconductor that activates the BNN6 species loaded on QD surfaces, leading to the effective NO production and the gas therapy in addition to the photothermal response. The increased accumulation of the NIR-II-responsive hybrid nanotheranostic in tumor via the enhanced permeation and retention effects was confirmed by both in vivo fluorescence and photoacoustic imaging. The prominent therapeutic efficacy of the photothermal/NO combination therapy from the BNN6-loaded AuS@QD nanodevice with the NIR-II laser irradiation at 1064 nm against 4T1 breast cancer was observed both in vitro and in vivo. The NO therapy for the cancer treatment was evidenced with the increased cellular nitrosative and oxidative stress, nitration of tyrosine residues of mitochondrial proteins, vessel eradication and cell apoptosis. The efficacy of the photothermal treatment was corroborated directly by severe tissue thermal ablation and tumor growth inhibition. The NIR-II triggered thermal/NO combination therapy along with the photoacoustic imaging-guided therapeutic accumulation in tumor shows prominent effect to fully inhibit tumor growth and validates the promising strategy developed in this study.

Ablative Radiotherapy Reprograms the Tumor Microenvironment of a Pancreatic Tumor in Favoring the Immune Checkpoint Blockade Therapy.

The low overall survival rate of patients with pancreatic cancer has driven research to seek a new therapeutic protocol. Radiotherapy (RT) is frequently an option in the neoadjuvant or palliative settings for pancreatic cancer treatment. This study explored the effect of RT protocols on the tumor microenvironment (TME) and their consequent impact on anti-programmed cell death ligand-1 (PD-L1) therapy. Using a murine orthotopic pancreatic tumor model, UN-KC-6141, RT-disturbed TME was examined by immunohistochemical staining. The results showed that ablative RT is more effective than fractionated RT at recruiting T cells. On the other hand, fractionated RT induces more myeloid-derived suppressor cell infiltration than ablative RT. The RT-disturbed TME presents a higher perfusion rate per vessel. The increase in vessel perfusion is associated with a higher amount of anti-PD-L1 antibody being delivered to the tumor. Animal survival is increased by anti-PD-L1 therapy after ablative RT, with 67% of treated animals surviving more than 30 days after tumor inoculation compared to a median survival time of 16.5 days for the control group. Splenocytes isolated from surviving animals were specifically cytotoxic for UN-KC-6141 cells. We conclude that the ablative RT-induced TME is more suited than conventional RT-induced TME to combination therapy with immune checkpoint blockade.

New combination treatment from ROS-Induced sensitized radiotherapy with nanophototherapeutics to fully eradicate orthotopic breast cancer and inhibit metastasis.

Radiotherapy (RT) is one of the most commonly employed approaches in the treatment of malignant tumors and is often combined with radiosensitizers to enhance the therapeutic efficacy for clinical use. For developing a smart therapeutic strategy leveraging local tissue response to photo-mediated reactions and the combination of multiple treatment modalities involving ROS-induced sensitization of RT, a novel nanophototherapeutic system has been developed. The nanotherapeutics prepared from the assembly of poly (thiodiethylene malonate) (PSDEM) and PEG-PSDEM-PEG and loaded with suberoylanilide hydroxamic acid (SAHA) employed as the RT sensitizer and indocyanine green (ICG) as the photothermal/photodynamic agent, demonstrated the capability of undergoing structural change and releasing therapeutic payloads in response to near-infrared irradiation and X-ray radiotherapy. With highly localized and controllable reactions within the tumor site, the reactive oxygen species (ROS)-triggered SAHA unloading and the hyperthermia-induced vascular permeability of oxygen led to a significant sensitization of the target tissue in RT, which, in turn, led to the promotion of therapeutic effect in conjunction with photodynamic/photothermal therapies (PDT/PTT). In vitro studies demonstrated the damage in intracellular DNA double strands and the inhibition of cell proliferation in 4T1 breast cancer cells treated with ROS-induced sensitized RT. A substantial reduction in cell viability was also observed owing to the effects of the combination of photo-mediated treatments with sensitized RT compared to the effects of RT administration alone. Complete eradication of the primary tumor and the inhibition of lung metastasis was observed in five of six orthotopic 4T1 breast cancer-bearing mice subjected to combined PDT/PTT in nanophototherapeutics with ROS-induced sensitized RT at a low dosage (6 Gy), leading to the prominent survival fraction of ca. 83% over 60 days.

Radiotherapy-Controllable Chemotherapy from Reactive Oxygen Species-Responsive Polymeric Nanoparticles for Effective Local Dual Modality Treatment of Malignant Tumors.

Radiotherapy is one of the general approaches to deal with malignant solid tumors in clinical treatment. To improve therapeutic efficacy, chemotherapy is frequently adopted as the adjuvant treatment in combination with radiotherapy. In this work, a reactive oxygen species (ROS)-responsive nanoparticle (NP) drug delivery system was developed to synergistically enhance the antitumor efficacy of radiotherapy by local ROS-activated chemotherapy, taking advantages of the enhanced concentration of reactive oxygen species (ROS) in tumor during X-ray irradiation and/or reoxygenation after X-ray irradiation. The ROS-responsive polymers, poly(thiodiethylene adipate) (PSDEA) and PEG-PSDEA-PEG, were synthesized and employed as the major components assembling in aqueous phase into polymer NPs in which an anticancer camptothecin analogue, SN38, was encapsulated. The drug-loaded NPs underwent structural change including swelling and partial dissociation in response to the ROS activation by virtue of the oxidation of the nonpolar sulfide residues in NPs into the polar sulfoxide units, thus leading to significant drug unloading. The in vitro performance of the chemotherapy from the X-ray irradiation preactivated NPs against BNL 1MEA.7R.1 murine carcinoma cells showed comparable cytotoxicity to free drug and appreciably enhanced effect on killing cancer cells while the X-ray irradiation being incorporated into the treatment. The in vivo tumor growth was fully inhibited with the mice receiving the local dual modality treatment of X-ray irradiation together with SN38-loaded NPs administered by intratumoral injection. The comparable efficacy of the local combinational treatment of X-ray irradiation with SN38-loaded NPs to free SN38/irradiation dual treatment corroborated the effectiveness of ROS-mediated drug release from the irradiated NPs at tumor site. The IHC examination of tumor tissues confirmed the significant reduction of VEGFA and CD31 expression with the tumor receiving the local dual treatment developed in this work, thus accounting for the absence of tumor regrowth compared to other single modality treatment.

Challenges of Using High-Dose Fractionation Radiotherapy in Combination Therapy.

Radiotherapy is crucial and substantially contributes to multimodal cancer treatment. The combination of conventional fractionation radiotherapy (CFRT) and systemic therapy has been established as the standard treatment for many cancer types. With advances in linear accelerators and image-guided techniques, high-dose fractionation radiotherapy (HFRT) is increasingly introduced in cancer centers. Clinicians are currently integrating HFRT into multimodality treatment. The shift from CFRT to HFRT reveals different effects on the tumor microenvironment and responses, particularly the immune response. Furthermore, the combination of HFRT and drugs yields different results in different types of tumors or using different treatment schemes. We have reviewed clinical trials and preclinical evidence on the combination of HFRT with drugs, such as chemotherapy, targeted therapy, and immune therapy. Notably, HFRT apparently enhances tumor cell killing and antigen presentation, thus providing opportunities and challenges in treating cancer.

Early Myocardial Repolarization Heterogeneity Is Detected by Magnetocardiography in Diabetic Patients with Cardiovascular Risk Factors.

Multi-channel magnetocardiography (MCG) is a sensitive technique to map spatial ventricular repolarization with high resolution and reproducibility. Spatial ventricular repolarization heterogeneity measured by MCG has been shown to accurately detect and localize myocardial ischemia. Here, we explored whether these measurements correlated with cardiovascular risk factors in patients with type 2 diabetes. Two hundreds and seventy-seven type 2 diabetic patients without known coronary artery disease (CAD) and arrhythmia were recruited consecutively from the outpatient clinic of National Taiwan University Hospital. The spatially distributed QTc contour maps were constructed with 64-channel MCG using the superconducting quantum interference device (SQUID) system. Indices of myocardial repolarization heterogeneity including the smoothness index of QTc (SI-QTc) and QTc dispersion were derived and analyzed for association with conventional cardiovascular risk factors. SI-QTc correlated strongly with the QTc dispersion (r = 0.70, p <0.0001). SI-QTc was significantly higher in patients with presence of metabolic syndrome in comparison to those without metabolic syndrome (8.56 vs. 7.96 ms, p = 0.02). In univariate correlation analyses, QTc dispersion was associated with smoking status (average 79.90, 83.83, 86.51, and 86.00 ms for never smokers, ex-smokers, current smokers reporting less than 10 cigarettes daily, and current smoker reporting more than 10 cigarettes daily, respectively, p = 0.03), body weight (r = 0.15, p = 0.01), and hemoglobin A1c (r = 0.12, p = 0.04). In stepwise multivariate regression analyses, QTc dispersion was associated with smoking (p = 0.02), body weight (p = 0.04), total cholesterol levels (p = 0.05), and possibly estimated glomerular filtration rate (p = 0.07). In summary, spatial heterogeneity of myocardial repolarization measured by MCG is positively associated cardiovascular risk factors including adiposity, smoking, and total cholesterol levels.

Effects of pre-irradiation and SDF-1 suppression on the progression of murine astrocytoma cells grown in different stromal beds.

PURPOSE: To examine whether brain tumors grown in pre-irradiated (PreIR) thigh have a similar tumor bed effect (TBE) as in PreIR brain tissue. MATERIAL AND METHODS: Tumor growth delay and immunohistochemical (IHC) staining for CD31, an endothelial surface marker, and PIMO, a hypoxia marker, were used to study the TBE of a murine astrocytoma, ALTS1C1, or a stromal-derived factor-1 (SDF-1) gene-silenced astrocytoma, ALTS1C1-SDFkd, growing in different PreIR stroma beds. RESULTS: ALTS1C1 tumors growing in both PreIR brain and PreIR thigh had reduced microvascular density (MVD) and more chronic hypoxia, but tumor growth delay was only seen in PreIR brain tissue. In contrast, ALTS1C1-SDFkd tumors showed tumor growth delay in PreIR thigh, with little effect in PreIR brain tissue. CONCLUSIONS: This study cautions that both the tumor and the nature of the PreIR stromal bed are important when using pre-irradiation as a model of recurrent brain tumors after radiation therapy.

Combination of vessel-targeting agents and fractionated radiation therapy: the role of the SDF-1/CXCR4 pathway.

PURPOSE: To investigate vascular responses during fractionated radiation therapy (F-RT) and the effects of targeting pericytes or bone marrow-derived cells (BMDCs) on the efficacy of F-RT. METHODS AND MATERIALS: Murine prostate TRAMP-C1 tumors were grown in control mice or mice transplanted with green fluorescent protein-tagged bone marrow (GFP-BM), and irradiated with 60 Gy in 15 fractions. Mice were also treated with gefitinib (an epidermal growth factor receptor inhibitor) or AMD3100 (a CXCR4 antagonist) to examine the effects of combination treatment. The responses of tumor vasculatures to these treatments and changes of tumor microenvironment were assessed. RESULTS: After F-RT, the tumor microvascular density (MVD) was reduced; however, the surviving vessels were dilated, incorporated with GFP-positive cells, tightly adhered to pericytes, and well perfused with Hoechst 33342, suggesting a more mature structure formed primarily via vasculogenesis. Although the gefitinib+F-RT combination affected the vascular structure by dissociating pericytes from the vascular wall, it did not further delay tumor growth. These tumors had higher MVD and better vascular perfusion function, leading to less hypoxia and tumor necrosis. By contrast, the AMD3100+F-RT combination significantly enhanced tumor growth delay more than F-RT alone, and these tumors had lower MVD and poorer vascular perfusion function, resulting in increased hypoxia. These tumor vessels were rarely covered by pericytes and free of GFP-positive cells. CONCLUSIONS: Vasculogenesis is a major mechanism for tumor vessel survival during F-RT. Complex interactions occur between vessel-targeting agents and F-RT, and a synergistic effect may not always exist. To enhance F-RT, using CXCR4 inhibitor to block BM cell influx and the vasculogenesis process is a better strategy than targeting pericytes by epidermal growth factor receptor inhibitor.