Image-guided in situ cancer vaccination with combination of multi-functional nano-adjuvant and an irreversible electroporation technique.

Cancer immunotherapy is a next-generation treatment strategy; however, its side effects limit its clinical translation. Here, a novel combination of a multi-functional nano-adjuvant (M-NA) prepared with an iron oxide/gold core and a cationic polymer shell via multilayer synthesis with CpG oligodeoxynucleotide (CpG-ODN) electrostatically complexed on its surface, and irreversible electroporation (IRE) technique was developed for effective image-guided in situ cancer vaccination. The M-NA can be retained long-term in the dense tumoral extracellular matrix after intratumoral injection and internalized by antigen-presenting cells (APCs). The IRE can induce immunogenic cell death. Indeed, in a mouse tumor model, the M-NA showed longer tumor retention time than free CpG-ODN. Compared with other treatments, the combined treatment significantly inhibited tumor growth with 100% survival rate for ∼60 days. The therapy induced the activation of cytotoxic lymphocytes and the maturation of APCs in vivo. This treatment could be effective in image-guided local cancer immunotherapy.

Development and Validation of Sorafenib-eluting Microspheres to Enhance Therapeutic Efficacy of Transcatheter Arterial Chemoembolization in a Rat Model of Hepatocellular Carcinoma.

Purpose: To validate the therapeutic efficacy of sorafenib-eluting embolic microspheres (SOR-EMs) used in combination with transarterial chemoembolization (TACE) for treatment of hepatocellular carcinoma (HCC) in a preclinical animal model. Materials and Methods: SOR-EMs were prepared with poly(d,l-lactide-co-glycolide), iron oxide nanoparticles, and sorafenib. The morphology of the prepared SOR-EMs was confirmed by using optical microscopy. Drug release from the SOR-EMs was quantified in vitro by using high-performance liquid chromatography. In an orthotopic rat model of HCC, embolic doxorubicin-Lipiodol (ethiodized oil) emulsion (DLE) and SOR-EMs were sequentially injected into the hepatic artery of the rats: The rats in group 1 were injected with DLE; group 2 was injected with DLE plus unloaded embolic microspheres (DLE + EM); group 3, with DLE plus SOR-EMs (DLE + SOR-EM); and group 4, with saline solution. The SOR-EM and tumor size changes in each group (of six rats each) over time were measured by using MRI. Tissues were assessed by using immunohistochemistry, with hematoxylin-eosin and terminal deoxynucleotidyl transferase-mediated dUTP (2'-deoxyuridine 5'-triphosphate) nick-end labeling staining used for dead cells and CD34 staining used for new microvessel formation. Results: The SOR-EMs were a mean size of 6.6 µm ± 2.3 (standard deviation) and showed 53.7% ± 8.3 sorafenib loading efficiency with T2-weighted MRI capability. In the HCC rat model, the intra-arterially injected SOR-EMs were successfully monitored by using MRI. The DLE + SOR-EM-treated rats showed a superior tumor growth-inhibitory effect compared with the rats treated with DLE only (P < .05). Immunohistochemical assessment of tissue specimens showed that compared with the other treatment groups, the DLE + SOR-EM treatment group had the lowest number of microvessels, as quantified by using the percentage of CD34-positive stained area (P < .01 for all comparisons). Conclusion: In a preclinical rat HCC model, SOR-EMs used in combination with DLE TACE were effective in treating HCC.Keywords: Chemoembolization, Experimental Investigations, Laboratory Tests, Liver, Technology Assessment Supplemental material is available for this article. © RSNA, 2021See also the commentary by Yamada and Gayed in this issue.

Long-acting nanoparticulate DNase-1 for effective suppression of SARS-CoV-2-mediated neutrophil activities and cytokine storm.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a new strain of coronavirus not previously identified in humans. Globally, the number of confirmed cases and mortality rates of coronavirus disease 2019 (COVID-19) have risen dramatically. Currently, there are no FDA-approved antiviral drugs and there is an urgency to develop treatment strategies that can effectively suppress SARS-CoV-2-mediated cytokine storms, acute respiratory distress syndrome (ARDS), and sepsis. As symptoms progress in patients with SARS-CoV-2 sepsis, elevated amounts of cell-free DNA (cfDNA) are produced, which in turn induce multiple organ failure in these patients. Furthermore, plasma levels of DNase-1 are markedly reduced in SARS-CoV-2 sepsis patients. In this study, we generated recombinant DNase-1-coated polydopamine-poly(ethylene glycol) nanoparticulates (named long-acting DNase-1), and hypothesized that exogenous administration of long-acting DNase-1 may suppress SARS-CoV-2-mediated neutrophil activities and the cytokine storm. Our findings suggest that exogenously administered long-acting nanoparticulate DNase-1 can effectively reduce cfDNA levels and neutrophil activities and may be used as a potential therapeutic intervention for life-threatening SARS-CoV-2-mediated illnesses.

Near-Infrared Fluorescent Endoscopic Image-Guided Photothermal Ablation Therapy of Colorectal Cancer Using Dual-Modal Gold Nanorods Targeting Tumor-Infiltrating Innate Immune Cells in a Transgenic TS4 CRE/APC loxΔ468 Mouse Model.

Colorectal cancer (CRC) is diagnosed with colonoscopy and treated with focal therapies. CRC is a good candidate for nanoparticle-mediated photothermal ablation (PTA) therapy. Herein, we developed a near-infrared fluorescent (NIRF) endoscopic image-guided PTA approach using a nanoparticle capable of simultaneously diagnosing and treating CRC. Dual-modal NIR heating and fluorescent gold nanorods (dual-modal GNRs) were synthesized by conjugation of GNRs to an NIRF probe. To validate the translational potential of our approach, a well-characterized transgenic TS4 CRE/APC loxΔ468 colon cancer mouse model was used to carry out NIRF image-guided PTA using our dual-modal GNRs under clinically relevant conditions. Intravenously infused dual-modal GNRs were effectively targeted at colon polyps by immunogenic capturing of the GNRs within tumor-infiltrating innate immune cells. NIRF endoscopic image-guided PTA using the GNRs permitted successful detection and ablation of inflammatory colon polyps. NIRF endoscopy image-guided PTA using dual-modal GNRs can be utilized for diagnosis and treatment of CRC and various inflammatory diseases.

Nanofunctionalized Stent-Mediated Local Heat Treatment for the Suppression of Stent-Induced Tissue Hyperplasia.

Current therapeutic strategies are insufficient for suppressing stent-induced restenosis. Here, branched gold nanoparticles (BGNP)-coated self-expandable metallic stents (SEMSs) were developed for a local heat-induced suppression of stent-related tissue hyperplasia. Our polydopamine (PDA) coating on SEMS allowed BGNP crystal growth on the surface of SEMSs. The prepared BGNP-coated SEMS showed effective local heating under near-infrared laser irradiation. The effectiveness of BGNP-coated SEMSs for suppressing stent-related tissue hyperplasia was demonstrated in a rat esophageal model ( n = 52). BGNP-coated SEMS placement under fluoroscopic guidance was technically successful in all rats. The placed BGNP-coated SEMS in rat esophagus achieved three different local heat dose ranges (50, 65, and 80 °C) under fluoroscopic image-guided local irradiation. Follow-up endoscopic examination readily monitored the local heating and observed significantly decreased tissue hyperplasia at 4 weeks of local heat treatments (50 and 65 °C). Finally, Western blot, histology, immunohistochemistry (HSP70, αSMA, and TUNEL), and immunofluorescence (Ki67 and BrdU) analyses along with the statistical analysis confirmed that optimized BGNP-coated SEMS-mediated local heat treatments inducing the expression of anti-inflammatory HSP70 effectively suppresses tissue hyperplasia after stent placement in the esophagus. Our local heating with nanofunctionalized stents represents a promising new approach for suppressing stent-related tissue hyperplasia.

Photosensitizer-Conjugated Hyaluronic Acid-Shielded Polydopamine Nanoparticles for Targeted Photomediated Tumor Therapy.

Photodynamic therapy (PDT) is a widely used clinical option for tumor therapy. However, the clinical utilization of conventional small-molecule photosensitizers (PSs) for PDT has been limited by their low selectivity for disease sites, and undesirable photoactivation. To overcome these limitations, we demonstrated a tumor-specific and photoactivity-controllable nanoparticle photomedicine based on a combination of PS-biomacromolecule conjugates and polydopamine nanoparticles (PD-NP) for an effective tumor therapy. This novel photomedicine consisted of a PD-NP core and a PS-conjugated hyaluronic acid (PS-HA) shell. The PD-NP and the PS-HA play roles as a quencher for PSs and a cancer targeting moiety, respectively. The synthesized PS-HA-shielded PD-NPs (PHPD-NPs) had a relatively narrow size distribution (approximately 130 nm) with uniform spherical shapes. In response to cancer-specific intracellular enzymes (e.g., hyaluronidase), the PHPD-NPs exhibited an excellent singlet oxygen generation capacity for PDT. Furthermore, an efficient photothermal conversion ability for photothermal therapy (PTT) was also shown in the PHPD-NPs system. These properties provide superior therapeutic efficacy against cancer cells. In mice tumor model, the photoactive restorative effects of the PHPD-NPs were much higher in cancer microenvironments compared to that in the normal tissue. As a result, the PHPD-NPs showed a significant antitumor activity in in vivo mice tumor model. The nanoparticle photomedicine design is a novel strategy for effective tumor therapy.

pH-sensitive nanoformulated triptolide as a targeted therapeutic strategy for hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) has one of the worst prognoses for survival as it is poorly responsive to both conventional chemotherapy and mechanism-directed therapy. This results from a lack of therapeutic concentration in the tumor tissue coupled with the highly toxic off-site effects exhibited by these compounds. Consequently, we believe the best packaging for holistic therapy for HCC will involve three components: a potent therapeutic, a rationally designed drug delivery vehicle to enrich the target site concentration of the drug, and a surface ligand that can enable a greater propensity to internalization by tumor cells compared to the parenchyma. We screened a library containing hundreds of compounds against a panel of HCC cells and found the natural product, triptolide, to be more effective than sorafenib, doxorubicin, and daunorubicin, which are the current standards of therapy. However, the potential clinical application of triptolide is limited due to its poor solubility and high toxicity. Consequently, we synthesized tumor pH-sensitive nanoformulated triptolide coated with folate for use in an HCC-subpopulation that overexpresses the folate receptor. Our results show triptolide itself can prevent disease progression, but at the cost of significant toxicity. Conversely, our pH-sensitive nanoformulated triptolide facilitates uptake into the tumor, and specifically tumor cells, leading to a further increase in efficacy while mitigating systemic toxicity.