How Did Conventional Nanoparticle-Mediated Photothermal Therapy Become "Hot" in Combination with Cancer Immunotherapy?

One of the promising cancer treatment methods is photothermal therapy (PTT), which has achieved good therapeutic efficiency through nanoparticle-based photoabsorbers. Because of the various functions of nanoparticles, such as targeting properties, high light-to-heat conversion, and photostability, nanoparticle-mediated PTT successfully induces photothermal damage in tumor tissues with minimal side effects on surrounding healthy tissues. The therapeutic efficacy of PTT originates from cell membrane disruption, protein denaturation, and DNA damage by light-induced heat, but these biological impacts only influence localized tumor areas. This conventional nanoparticle-mediated PTT still attracts attention as a novel cancer immunotherapy, because PTT causes immune responses against cancer. PTT-induced immunogenic cell death activates immune cells for systemic anti-cancer effect. Additionally, the excellent compatibility of PTT with other treatment methods (e.g., chemotherapy and immune checkpoint blockade therapy) reinforces the therapeutic efficacy of PTT as combined immunotherapy. In this review, we investigate various PTT agents of nanoparticles and compare their applications to reveal how nanoparticle-mediated PTT undergoes a transition from thermotherapy to immunotherapy.

Bovine colostrum derived-exosomes prevent dextran sulfate sodium-induced intestinal colitis via suppression of inflammation and oxidative stress.

Despite the rise in the global burden of inflammatory bowel disease, there is a lack of safe and effective therapies that can meet the needs of clinical patients. In this study, we investigated the beneficial effects of bovine milk, especially colostrum-derived exosomes (Col-exo) in a murine model of ulcerative colitis induced by dextran sodium sulfate (DSS). Col-exo activated the proliferation of colonic epithelial cells and macrophages, and created an environment to relieve inflammation by effectively removing reactive oxygen species and regulating the expression of immune cytokines. Besides, Col-exo could pass through the gastrointestinal tract intact and efficiently deliver bioactive cargoes to the stomach, small intestine, and colon. Our results showed that oral gavage of Col-exo can alleviate colitis symptoms including weight loss, gastrointestinal bleeding, and chronic diarrhea by modulating intestinal inflammatory immune responses. Overall, bovine colostrum-derived exosomes with excellent structural and functional stability may offer great potential as natural therapeutics for the recovery of colitis.

Enhanced proliferation of rabbit chondrocytes by using a well circulated nanoshock system.

The gold nanorods (GNRs) embedded alginate-chitosan (scaffold), which was designed and fabricated to produce efficient handling of the cell proliferations. Scaffold embedded GNR (SGNR) and NIR (near infrared) irradiations are developing into an interesting medical prognosis tool for rabbit chondrocyte (RC) proliferation. SGNR contained a pattern of uniform pores. Biocompatibility and cellular proliferation achieved by disclosures to NIR irradiations, providing high cell survival. SGNR and NIR irradiations could produce mechanical and biochemical cues for regulating RCs proliferations. To determine the thermal stress, it exposed RCs to 39-42 °C for 0-240 min at the start point of the cell culture cycle. It produced photothermal stress in cellular surrounding (cells located adjacent to and within scaffold) and it deals with the proliferation behavior of RC. All the processes were modeled with experimental criteria and time evolution process. Our system could help the cell proliferation by generating heat for cells. Hence, the present strategy could be implemented for supporting cell therapeutics after transplantation. This implementation would open new design techniques for integrating the interfaces between NIR irradiated and non-irradiated tissues.

Heat-Generating Iron Oxide Multigranule Nanoclusters for Enhancing Hyperthermic Efficacy in Tumor Treatment.

The development of heat-generating magnetic nanostructures is critical for the effective management of tumors using magnetic hyperthermia. Herein, we demonstrate that polyethylene glycol (PEG)-coated iron oxide (magnetite, Fe3O4) multigranule nanoclusters (PEG-MGNCs) can enhance the efficiency of hyperthermia-based tumor suppression in vitro and in vivo. MGNCs consisting of granules (crystallites) measuring 22.9 nm in diameter were prepared via the hydrothermal polyol method, followed by the surface modification of MGNCs with PEG-dopamine. The freshly prepared PEG-MGNCs exhibit 145.9 ± 10.2 nm diameter on average under aqueous conditions. The three-dimensional structures of PEG-MGNCs enhance the hyperthermic efficacy compared with PEGylated single iron-oxide nanoparticles (NPs), resulting in severe heat damage to tumor cells in vitro. In the SCC7 tumor-bearing mice, near-infrared fluorescence dye (Cy5.5)-labeled PEG-MGNCs are successfully accumulated in the tumor tissues because of NP-derived enhanced permeation and retention effect. Finally, the tumor growth is significantly suppressed in PEG-MGNC-treated mice after two-times heat generation by using a longitudinal solenoid, which can generate an alternating magnetic field under high-frequency (19.5 kA/m, 389 kHz) induction. This study shows for the first time that the PEG-MGNCs greatly enhance the hyperthermic efficacy of tumor treatment both in vitro and in vivo.

Engineered Zn(II)-Dipicolylamine-Gold Nanorod Provides Effective Prostate Cancer Treatment by Combining siRNA Delivery and Photothermal Therapy.

Combination cancer treatment has emerged as a critical approach to achieve remarkable anticancer effect. In this study, we prepared a theranostic nanoformulation that allows for photoacoustic imaging as well as combination gene and photothermal therapy. Gold nanorods (GNR) were coated with dipicolyl amine (DPA), which forms stable complexes with Zn2+ cations. The resulting nanoparticles, Zn(II)/DPA-GNR, recognize phosphate-containing molecules, including siRNA, because of the specific interaction between Zn(II) and the phosphates. We chose anti-polo-like kinase 1 siRNA (siPLK) as our example for gene silencing. The strong complexation between Zn(II)/DPA-GNR and siPLK provided high stability to the nano-complexes, which efficiently delivered siRNA into the targeted cancer cells in vitro and in vivo. The particle served as a theranostic agent because the GNRs of nano-complexes permitted effective photothermal therapy as well as photoacoustic imaging upon laser irradiation. This gene/photothermal combination therapy using siPLK/Zn(II)DPA-GNRs exhibited significant antitumor activity in a PC-3 tumor mouse model. The concept described in this work may be extended to the development of efficient delivery strategies for other polynucleotides as well as advanced anticancer therapy.

Superparamagnetic Gold Nanoparticles Synthesized on Protein Particle Scaffolds for Cancer Theragnosis.

Cancer theragnosis using a single multimodality agent is the next mainstay of modern cancer diagnosis, treatment, and management, but a clinically feasible agent with in vivo cancer targeting and theragnostic efficacy has not yet been developed. A new type of cancer theragnostic agent is reported, based on gold magnetism that is induced on a cancer-targeting protein particle carrier. Superparamagnetic gold-nanoparticle clusters (named SPAuNCs) are synthesized on a viral capsid particle that is engineered to present peptide ligands targeting a tumor cell receptor (TCR). The potent multimodality of the SPAuNCs is observed, which enables TCR-specific targeting, T2 -weighted magnetic resonance imaging, and magnetic hyperthermia therapy of both subcutaneous and deep-tissue tumors in live mice under an alternating magnetic field. Furthermore, it is analytically elucidated how the magnetism of the SPAuNCs is sufficiently induced between localized and delocalized spins of Au atoms. In particular, the SPAuNCs show excellent biocompatibility without the problem of in vivo accumulation and holds promising potential as a clinically effective agent for cancer theragnosis.

Antitumor therapeutic application of self-assembled RNAi-AuNP nanoconstructs: Combination of VEGF-RNAi and photothermal ablation.

Nucleic acid-directed self-assembly provides an attractive method to fabricate prerequisite nanoscale structures for a wide range of technological applications due to the remarkable programmability of DNA/RNA molecules. In this study, exquisite RNAi-AuNP nanoconstructs with various geometries were developed by utilizing anti-VEGF siRNA molecules as RNAi-based therapeutics in addition to their role as building blocks for programmed self-assembly. In particular, the anti-VEGF siRNA-functionalized AuNP nanoconstructs can take additional advantage of gold-nanoclusters for photothermal cancer therapeutic agent. A noticeable technical aspect of self-assembled RNAi-AuNP nanoconstructs in this study is the precise conjugation and separation of designated numbers of therapeutic siRNA onto AuNP to develop highly sophisticated RNA-based building blocks capable of creating various geometries of RNAi-AuNP nano-assemblies. The therapeutic potential of RNAi-AuNP nanoconstructs was validated in vivo as well as in vitro by combining heat generation capability of AuNP and anti-angiogenesis mechanism of siRNA. This strategy of combining anti-VEGF mechanism for depleting angiogenesis process at initial tumor progression and complete ablation of residual tumors with photothermal activity of AuNP at later tumor stage showed effective tumor growth inhibition and tumor ablation with PC-3 tumor bearing mice.

Inorganic Nanoparticles for Image-Guided Therapy.

Recently, nanotechnology has provided significant advances in biomedical applications including diagnosis and therapy. In particular, nanoparticles have emerged as valuable outcomes of nanotechnology due to their unique physicochemical properties based on size, shape, and surface properties. Among them, a large amount of research has reported imaging and therapeutic applications using inorganic nanoparticles with special properties. Inorganic nanoparticles developed for imaging and therapy contain metal (Au), metal oxide (Fe3O4, WO3, WO2.9), semiconductor nanocrystal (quantum dots (QDs)), and lanthanide-doped upconversion nanoparticles (UCNPs). Based on their intrinsic properties, they can generate heat, reactive oxygen species (ROS), or energy transfer, so that they can be used for both imaging and therapy. In this review, we introduce biocompatible inorganic nanoparticles for image-guided thermal and photodynamic therapy, and discuss their promising results from in vitro and in vivo studies for biomedical applications.

Improvement of Antitumor Efficacy by Combination of Thermosensitive Liposome with High-Intensity Focused Ultrasound.

High intensity focused ultrasound (HIFU), allowing for precise heating of the deep and local area, is emerging as the source of mild hyperthermia for delivery of doxorubicin (DOX) using thermosensitive liposomes (TSLs). Conventionally, HIFU has been used for intravascular drug release at tumor tissue by inducing mild hyperthermia immediately upon systemic administration of DOX-TSLs. This immediate heating approach (IHA), however, limits the deep penetration of DOX for high anticancer efficacy. In an attempt to maximize the accumulation of DOX at tumor, the delayed heating approach (DHA) has been explored. In this approach, DOX-TSLs were intravenously administered into the tumor-bearing mice after pre-treatment of tumor tissue with HIFU to increase vascular permeability. We developed the fatty acid-cojugated elastinlike polypeptide bearing TSL (FTSL). The DOX-loaded FTSLs had a hydrodynamic size of 142 nm. In vivo biodistribution study demonstrated that DOX-FTSLs were selectively accumulated at tumor tissue with the maximum amount of DOX at 6 h post-injection. Thereafter, the tumor tissue was heated to 42 °C to induce rapid release of DOX from FTSLs. The results have demonstrated that, compared to IHA, DHA significantly enhances the antitumor efficacy of DOX-FTSLs because of their effective penetration to tumor tissue via the enhanced permeation retention effect, followed by rapid release of DOX.

Systemic PEGylated TRAIL treatment ameliorates liver cirrhosis in rats by eliminating activated hepatic stellate cells.

UNLABELLED: Liver fibrosis is a common outcome of chronic liver disease that leads to liver cirrhosis and hepatocellular carcinoma. No US Food and Drug Administration-approved targeted antifibrotic therapy exists. Activated hepatic stellate cells (aHSCs) are the major cell types responsible for liver fibrosis; therefore, eradication of aHSCs, while preserving quiescent HSCs and other normal cells, is a logical strategy to stop and/or reverse liver fibrogenesis/fibrosis. However, there are no effective approaches to specifically deplete aHSCs during fibrosis without systemic toxicity. aHSCs are associated with elevated expression of death receptors and become sensitive to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced cell death. Treatment with recombinant TRAIL could be a potential strategy to ameliorate liver fibrosis; however, the therapeutic application of recombinant TRAIL is halted due to its very short half-life. To overcome this problem, we previously generated PEGylated TRAIL (TRAILPEG ) that has a much longer half-life in rodents than native-type TRAIL. In this study, we demonstrate that intravenous TRAILPEG has a markedly extended half-life over native-type TRAIL in nonhuman primates and has no toxicity in primary human hepatocytes. Intravenous injection of TRAILPEG directly induces apoptosis of aHSCs in vivo and ameliorates carbon tetrachloride-induced fibrosis/cirrhosis in rats by simultaneously down-regulating multiple key fibrotic markers that are associated with aHSCs. CONCLUSION: TRAIL-based therapies could serve as new therapeutics for liver fibrosis/cirrhosis and possibly other fibrotic diseases. (Hepatology 2016;64:209-223).

Effect of HIFU treatment on tumor targeting efficacy of docetaxel-loaded Pluronic nanoparticles.

Numerous studies have been performed to identify the microenvironment of solid tumors, which is responsible for the insufficient delivery of anticancer drugs to tumor cells due to the poorly organized vasculature and the increased interstitial fluid pressure. As a result, the extravasation of convection-dependent agents including NPs is severely limited. Therefore, we have demonstrated the feasibility of targeting an enhancement of docetaxel-loaded Pluronic nanoparticles (NPs) using high-intensity focused ultrasound (HIFU) as an external stimulus-induced clinical system in tumor tissue. The efficient extravasation of NPs into the interior cells in tumor tissue was induced by relatively low HIFU exposure without apparent acute tissue damage. The enhanced targeting of NPs with near-infrared fluorescence dye was observed in tumor-bearing mice with various HIFU exposures. As a result, the greatest accumulation of NPs at the tumor tissue was observed at an HIFU exposure of 20 W/cm(2). However, the tumor tissue above at 20 W/cm(2) appeared to be destroyed and the tumor targetability of NPs was significantly decreased owing to thermal ablation with necrosis, resulting in the destruction of the tumor tissue and the blood vessels. In particular, a cross-sectional view of the tumor tissue verified that the NPs migrated into the middle of the tumor tissue upon HIFU exposure. The preliminary results here demonstrate that HIFU exposure through non-thermal mechanisms can aid with the extravasation of NPs into the interior cells of tumors and increase the therapeutic effect in enhanced and targeted cancer therapy.

Prevention effect of orally active heparin conjugate on cancer-associated thrombosis.

Thrombogenesis is a major cause of morbidity and mortality in cancer patients. Prophylaxis with low-molecular-weight heparin (LMWH) is recommended for cancer patients, but requires non-parenteral delivery methods for long-term treatments. In this study, we sought to generate a new oligomeric-bile acid conjugate of LMWH that can be used for oral delivery. We first synthesized a tetramer of deoxycholic acid (tetraDOCA), which was site-specifically conjugated at the end saccharide of LMWH. When LMWH-tetraDOCA conjugate (LHe-tetraD) was orally administered at a dose of 5 mg/kg in ICR mice, the maximum anti-factor Xa level was increased up to 0.62±0.05 IU/mL without any evidence of liver toxicity, gastrointestinal damage, or thrombocytopenia. The cancer-associated thrombosis was induced in tumor-bearing mice by local heat application, and the fibrin deposition in tumors was evaluated. The oral administration of LHe-tetraD (either a single dose or multiple daily doses for up to 10 days) in mice substantially abolished the coagulation-dependent tropism of fibrinogen in the heated tumors and significantly decreased hemorrhage, compared to the mice treated with saline or subcutaneous injection of LMWH. Thus, the anticoagulation effect of oral LHe-tetraD invokes the benefits of oral delivery and promises to provide an effective and convenient treatment for cancer patients at risk of thrombosis.

Silica coated gold nanorods for imaging and photo-thermal therapy of cancer cells.

Due to their efficient conversion of absorbed light energy to heat gold nanorods have been proved to be an amazing tool for minimally invasive photo-thermal cancer therapy. The present in vitro study demonstrates the ability of silica coated Au nanorods to function as a dual probe for cancer-cell therapy and imaging without any toxic side-effects. HeLa cells were incubated with silica coated Au nanorods and imaged inside the cell just after 1 hour of incubation by a dark field set up due to strong surface enhanced Raman scattering. To induce hyperthermia, silica coated Au nanorod incubated HeLa cells were illuminated with a diode laser (671 nm, 200 mW, 10 min). Cell destruction was observed even at a very low dose of nanorods, whereas none was observed in the absence of nanorods. Silica coated Au nanorods thus offer a promising, novel class of selective photo-thermal agents for cancer therapy and diagnosis.

Blood-pool multifunctional nanoparticles formed by temperature-induced phase transition for cancer-targeting therapy and molecular imaging.

Multifunctional nanoparticles (NPs) were prepared based on temperature-induced phase transition in a molten mixture of Lipiodol(®), Tween 80, paclitaxel (PTX), and Pluronic F-68, wherein the Lipiodol(®)/Tween 80 mixture is used as a solubilizer for PTX, and Pluronic F-68 is used for the stabilization of the molten mixture. The morphology and size distribution of optimized multifunctional NPs were observed using transmittance electron microscopy (TEM) and a particle size analyzer. In the optical imaging of tumor-bearing mice using a near-infrared fluorescence (NIRF) imaging system, the multifunctional NPs were evaluated in terms of a time-dependent excretion profile, in vivo biodistribution and tumor-targeting capability compared to free fluorescence dye. In addition, the prolonged circulation of multifunctional NPs was confirmed by enhancement of the blood-pool in live animals using a micro-CT imaging system, because iodine-containing Lipiodol(®) has an X-ray enhancement property. Finally, the anti-tumor efficacy of multifunctional NPs was monitored by injecting the multifunctional NPs into the tail veins of tumor-bearing mice. The multifunctional NPs showed excellent tumor targetability and anti-tumor efficacy in tumor-bearing mice, caused by the enhanced permeation and retention (EPR) effect.

Tumor-targeting multi-functional nanoparticles for theragnosis: new paradigm for cancer therapy.

Theragnostic nanoparticles (NPs) contain diagnostic and therapeutic functions in one integrated system, enabling diagnosis, therapy, and monitoring of therapeutic response at the same time. For diagnostic function, theragnostic NPs require the inclusion of noninvasive imaging modalities. Among them, optical imaging has various advantages including sensitivity, real-time and convenient use, and non-ionization safety, which make it the leading technique for theragnostic NPs. For therapeutic function, theragnostic NPs have been applied to chemotherapy, photodynamic therapy, siRNA therapy and photothermal therapy. In this review, we present a recent progress reported in the development and applications of theragnostic NPs for cancer therapy. More specifically, we will focus on theragnostic NPs related with optical imaging, highlighting promising strategies based on optical imaging techniques.

Matrix metalloproteinase sensitive gold nanorod for simultaneous bioimaging and photothermal therapy of cancer.

Herein, we developed matrix metalloprotease (MMP) sensitive gold nanorods (MMP-AuNR) for cancer imaging and therapy. It was feasible to absorb NIR laser and convert into heat as well as visualize MMP activity. We showed the possibility of gold nanorods as a hyperthermal therapeutic agent and MMP sensitive imaging agent both in vitro and in vivo condition. The results suggested potential application of MMP-AuNR for simultaneous cancer diagnosis and therapy.