Safe and Efficient Molybdenum Disulfide Platform for Cooperative Imaging-Guided Photothermal-Selective Chemotherapy: A Preclinical Study

Abstract Background The striking imbalance between the ever-increasing amount of nanomedicines and low clinical translation of products has become the focus of intense debate. For clinical translation, the critical issue is to select the appropriate agents and combination regimen for targeted diseases, not to prepare increasingly complex nanoplatforms. Methods Herein, a safe and efficient platform, α-tocopheryl succinate (α-TOS) married 2D molybdenum disulfide, was devised by a facile method and applied for cooperative imaging-guided photothermal-selective chemotherapy of ovarian carcinoma. Results The photothermal efficiency (65.3%) of the platform under safe near-infrared irradiation is much higher than that of other photothermal materials reported elsewhere. Moreover, the covalently linked α-TOS renders platform with selective chemotherapy for cancer cells. Remarkably, with these excellent properties, the platform can be used to completely eliminate the solid tumor by safe photothermal therapy, and then kill the residual cancer cells by selective chemotherapy to prevent tumor recurrence. More significantly, barely side effects occurred in the whole treatment process. The excellent efficacy and safety benefits in vivo lead to the prominent survival rate of 100% over 91 days. Conclusion Overall, the safe and efficient platform might be a candidate of clinical nanomedicines for multimode theranostics. This study demonstrates an innovative thought in precise nanomedicine regarding the design of next generation of cancer theranostic protocol for potential clinical practice.

Download Full-text

[Mn(PaPy2Q)(NO)]ClO4, a Near-Infrared Light activated release of Nitric Oxide drug as a nitric oxide donor for therapy of human prostate cancer cells in vitro and in vivo

Biomedicine & Pharmacotherapy ◽

10.1016/j.biopha.2021.111388 ◽

2021 ◽

Vol 137 ◽

pp. 111388

Author(s):

Yuwan Zhao ◽

Zhuo Li ◽

Huancheng Tang ◽

Shanhong Lin ◽

Wenfeng Zeng ◽

...

Keyword(s):

Prostate Cancer ◽

Nitric Oxide ◽

Cancer Cells ◽

Near Infrared ◽

Nitric Oxide Donor ◽

Infrared Light ◽

Human Prostate Cancer ◽

Prostate Cancer Cells

Download Full-text

Fibroblast activation protein targeted near infrared photoimmunotherapy (NIR PIT) overcomes therapeutic resistance in human esophageal cancer

Scientific Reports ◽

10.1038/s41598-021-81465-4 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Ryoichi Katsube ◽

Kazuhiro Noma ◽

Toshiaki Ohara ◽

Noriyuki Nishiwaki ◽

Teruki Kobayashi ◽

...

Keyword(s):

Esophageal Cancer ◽

Cancer Cells ◽

Cancer Progression ◽

Near Infrared ◽

Fibroblast Activation Protein ◽

Therapeutic Resistance ◽

Fibroblast Activation ◽

Human Esophageal Cancer

AbstractCancer-associated fibroblasts (CAFs) have an important role in the tumor microenvironment. CAFs have the multifunctionality which strongly support cancer progression and the acquisition of therapeutic resistance by cancer cells. Near-infrared photoimmunotherapy (NIR-PIT) is a novel cancer treatment that uses a highly selective monoclonal antibody (mAb)-photosensitizer conjugate. We developed fibroblast activation protein (FAP)-targeted NIR-PIT, in which IR700 was conjugated to a FAP-specific antibody to target CAFs (CAFs-targeted NIR-PIT: CAFs-PIT). Thus, we hypothesized that the control of CAFs could overcome the resistance to conventional chemotherapy in esophageal cancer (EC). In this study, we evaluated whether EC cell acquisition of stronger malignant characteristics and refractoriness to chemoradiotherapy are mediated by CAFs. Next, we assessed whether the resistance could be rescued by eliminating CAF stimulation by CAFs-PIT in vitro and in vivo. Cancer cells acquired chemoradiotherapy resistance via CAF stimulation in vitro and 5-fluorouracil (FU) resistance in CAF-coinoculated tumor models in vivo. CAF stimulation promoted the migration/invasion of cancer cells and a stem-like phenotype in vitro, which were rescued by elimination of CAF stimulation. CAFs-PIT had a highly selective effect on CAFs in vitro. Finally, CAF elimination by CAFs-PIT in vivo demonstrated that the combination of 5-FU and NIR-PIT succeeded in producing 70.9% tumor reduction, while 5-FU alone achieved only 13.3% reduction, suggesting the recovery of 5-FU sensitivity in CAF-rich tumors. In conclusion, CAFs-PIT could overcome therapeutic resistance via CAF elimination. The combined use of novel targeted CAFs-PIT with conventional anticancer treatments can be expected to provide a more effective and sensible treatment strategy.

Download Full-text

Selection of the First 99mTc-Labelled Somatostatin Receptor Subtype 2 Antagonist for Clinical Translation—Preclinical Assessment of Two Optimized Candidates

Pharmaceuticals ◽

10.3390/ph14010019 ◽

2020 ◽

Vol 14 (1) ◽

pp. 19

Author(s):

Melpomeni Fani ◽

Viktoria Weingaertner ◽

Petra Kolenc Peitl ◽

Rosalba Mansi ◽

Raghuvir H. Gaonkar ◽

...

Keyword(s):

Protein Binding ◽

Somatostatin Receptor ◽

Somatostatin Receptors ◽

Preclinical Study ◽

Clinical Translation ◽

Hek293 Cells ◽

Neuroendocrine Neoplasms ◽

Receptor Subtype ◽

Selection Of

Recently, radiolabelled antagonists targeting somatostatin receptors subtype 2 (SST2) in neuroendocrine neoplasms demonstrated certain superior properties over agonists. Within the ERA-PerMED project “TECANT” two 99mTc-Tetramine (N4)-derivatized SST2 antagonists (TECANT-1 and TECANT-2) were studied for the selection of the best candidate for clinical translation. Receptor-affinity, internalization and dissociation studies were performed in human embryonic kidney-293 (HEK293) cells transfected with the human SST2 (HEK-SST2). Log D, protein binding and stability in human serum were assessed. Biodistribution and SPECT/CT studies were carried out in nude mice bearing HEK-SST2 xenografts, together with dosimetric estimations from mouse-to-man. [99mTc]Tc-TECANT-1 showed higher hydrophilicity and lower protein binding than [99mTc]-TECANT-2, while stability was comparable. Both radiotracers revealed similar binding affinity, while [99mTc]Tc-TECANT-1 had higher cellular uptake (>50%, at 2 h/37 °C) and lower dissociation rate (<30%, at 2 h/37 °C). In vivo, [99mTc]Tc-TECANT-1 showed lower blood values, kidney and muscles uptake, whereas tumour uptake was comparable to [99mTc]Tc-TECANT-2. SPECT/CT imaging confirmed the biodistribution results, providing the best tumour-to-background image contrast for [99mTc]Tc-TECANT-1 at 4 h post-injection (p.i.). The estimated radiation dose amounted to approximately 6 µSv/MBq for both radiotracers. This preclinical study provided the basis of selection of [99mTc]Tc-TECANT-1 for clinical translation of the first 99mTc-based SST2 antagonist.

Download Full-text

PEGylated nickel carbide nanocrystals as efficient near-infrared laser induced photothermal therapy for treatment of cancer cells in vivo

Nanoscale ◽

10.1039/c4nr03727h ◽

2014 ◽

Vol 6 (21) ◽

pp. 12591-12600 ◽

Cited By ~ 19

Author(s):

Zhiguo Zhou ◽

Jun Wang ◽

Wei Liu ◽

Chao Yu ◽

Bin Kong ◽

...

Keyword(s):

Cancer Cells ◽

Photothermal Therapy ◽

Near Infrared ◽

Infrared Laser ◽

Nickel Carbide

Download Full-text

Cellular immunotherapy redirected by bispecific antibodies in primary ovarian cancer cells: A preclinical study

Journal of Clinical Oncology ◽

10.1200/jco.2006.24.18_suppl.2518 ◽

2006 ◽

Vol 24 (18_suppl) ◽

pp. 2518-2518

Author(s):

J. K. Chan ◽

C. A. Hamilton ◽

M. K. Cheung ◽

S. Schulz ◽

S. H. Thorne ◽

...

Keyword(s):

Ovarian Cancer ◽

Cancer Cells ◽

Randomized Clinical Trials ◽

Preclinical Study ◽

Bispecific Antibodies ◽

Cellular Immunotherapy ◽

Ovarian Cancer Cells ◽

Primary Ovarian Cancer ◽

Cik Cells

2518 Background: Cytokine induced killer cells (CIKs) are ex-vivo activated and expanded CD8+ natural killer T cells that have been shown to have cytotoxic activity against cancers in randomized clinical trials. This preclinical study demonstrates the enhanced effect of CIK killing in primary ovarian carcinoma using bispecific antibodies (BSAbs) and the potential of translating our findings to a clinical trial. Methods: Primary ovarian cancer cells and autologous CIKs were collected and cultured under IRB approval. Cytotoxicity enhancing BSAbs against CA125 (BSAbxCA125) and Her2/neu (BSAbxHer2) were designed using chemical conjugation methods. Tumor cell lysis of ovarian primary ovarian cancer cells was quantified using 51Cr release assays. Anti-NKG2D monoclonal antibodies were used in antibody blocking assays. Using a SCID mouse model of minimal residual disease, tumor progression was monitored using the bioluminescence imaging (BLI) system. Three-color immunofluorescence analysis was performed on pathologic specimens to localize CIK migration to tumor cells. Results: The mean percent lysis with an Effector:Target (E:T) ratio at 100:1 was 22.2% (±2.0) in primary cells in 4-hour killing assays. Redirection with BSAbxCA125 significantly enhanced cytolysis to 65.7% (±0.6). Adding BSAbxHer2 significantly enhanced cytolysis of cell lines to 89.4% (±1.3). Anti-NKG2D antibodies significantly attenuated the CIK activity by 54%. In vivo BLI studies in SCID mice showed that CIK treatment at a 10:1 E:T ratio was well-tolerated and effective in reducing tumor burden by 80% after 21 days post-treatment compared to untreated mice (p<0.0001). Immunofluorescence staining clearly depicted the in vivo infiltration of CIK (CD8+NKG2D+) cells into Her2-expressing tumor targets. Conclusions: Bispecific antibodies effectively enhanced the cytotoxicity of autologous CIK cells against fresh ovarian tumors. Our in vivo studies suggest that CIK cells may ultimately prove to be efficacious immunotheraputic modality in the treatment of resistant ovarian cancer. No significant financial relationships to disclose.

Download Full-text

Identification of a mitochondria-targeting fluorescent small molecule for dual phototherapy

Journal of Innovative Optical Health Sciences ◽

10.1142/s1793545818500165 ◽

2018 ◽

Vol 11 (04) ◽

pp. 1850016 ◽

Cited By ~ 2

Author(s):

Jie Chen ◽

Xu Tan ◽

Shenglin Luo ◽

Lei Long ◽

Lang Liu ◽

...

Keyword(s):

Cancer Cells ◽

Small Molecule ◽

Near Infrared ◽

Significant Inhibition ◽

Cytotoxicity Studies ◽

Inhibition Of Tumor Growth ◽

High Cytotoxicity ◽

Mitochondria Targeting

Phototherapy, mainly including photodynamic therapy (PDT) and photothermal therapy (PTT), is a noninvasive and effective approach for cancer treatment. Since integration of PDT and PTT for simultaneous synergistic PDT/PTT treatment enables us to improve phototherapeutic efficacy significantly, it has been attracting a lot of investigations in current days. Here, we introduce IR-52, a new mitochondria-targeting near infrared (NIR) fluorescent small molecule, which possesses structure-inherent PTT and PDT synergistic phototherapeutic effects without conjugation to specific ligands. After NIR light irradiation (808[Formula: see text]nm, 2[Formula: see text]W/cm2, 5[Formula: see text]min), both the hyperthermia and excessive singlet oxygen levels were determined when dissolving IR-52 in aqueous solutions. In vitro photoinduced cytotoxicity studies showed significant lower cell viabilities and higher necrotic/apoptotic rates when cancer cells were treated with IR-52 and irradiation, and its’ mitochondrial localization in cancer cells would partially explain its high cytotoxicity. Further in vivo synergetic PDT and PTT effects were demonstrated by high tumor surface temperature and significant inhibition of tumor growth. Our results strongly suggest that IR-52, which possesses excellent photosensitivity, may provide a promising strategy for tumor treatment with decreased side effects.

Download Full-text

Injectable Thermosensitive Chitosan Solution with β-Glycerophosphate as an Optimal Submucosal Fluid Cushion for Endoscopic Submucosal Dissection

Polymers ◽

10.3390/polym13111696 ◽

2021 ◽

Vol 13 (11) ◽

pp. 1696

Author(s):

Seung Jeong ◽

Han Jo Jeon ◽

Kyoung-Je Jang ◽

Sangbae Park ◽

Hyuk Soon Choi ◽

...

Keyword(s):

Endoscopic Submucosal Dissection ◽

Chitosan Solution ◽

Critical Issue ◽

Preclinical Study ◽

Commercial Products ◽

Viscosity Change ◽

Submucosal Injection ◽

Submucosal Dissection ◽

Low Cytotoxicity

Endoscopic submucosal dissection (ESD) is a surgical procedure to remove early neoplastic lesions in the gastrointestinal tract with the critical issue of perforation. A submucosal fluid cushion, such as normal saline, is used as a cushioning agent to prevent perforation; however, its cushioning maintenance is insufficient for surgery. In this study, we introduce an injectable thermosensitive chitosan solution (CS) with β-glycerophosphate (β-GP) as a submucosal injection agent for ESD. The CS/β-GP system with optimal β-GP concentration showed drastic viscosity change near body temperature while other commercial products did not. Additionally, the injectability of the solution was similar to or greater than other commercial products. The solution with low β-GP concentration showed low cytotoxicity similar to other products. An in vivo preclinical study illustrated maintenance of the high cushioning of the thermosensitive solutions. These results indicate that a CS/β-GP system with optimal β-GP concentration might be used as a submucosal injection agent in ESD, and further studies are needed to validate the effectiveness of the solutions in vivo.

Download Full-text

An internal cross-linked polymeric nanoparticle with dual sensitivity for combination therapy of muscle-invasive bladder cancer

10.21203/rs.3.rs-29953/v3 ◽

2020 ◽

Author(s):

Guanchen Zhu ◽

Kaikai Wang ◽

Haixiang Qin ◽

Xiaozhi Zhao ◽

Wei Chen ◽

...

Keyword(s):

Bladder Cancer ◽

Cancer Cells ◽

Laser Irradiation ◽

Tumor Cells ◽

Tumor Targeting ◽

Near Infrared ◽

Infrared Laser ◽

Infrared Laser Irradiation ◽

Targeting Ability

Abstract Chemotherapy is a standard cancer treatment which uses anti-cancer drugs to destroy or slow the growth of cancer cells. However, chemotherapy has limited therapeutic effects in bladder cancer. One of the reasons of this resistance to chemotherapy is that higher levels of glutathione in invasive bladder cancer cells. We have fabricated nanoparticles that respond to high concentrations of glutathione and near-infrared laser irradiation in order to increase the drug accumulation at the tumor sites and combine chemotherapy with photothermal therapy to overcome the challenges of bladder cancer treatment.Methods:The DOX&IR780@PEG-PCL-SS NPs were prepared by co-precipitation method. We investigated the tumor targeting capability of NPs in vitro and in vivo. The orthotopic bladder cancer model in C57BL/6 mice was established for in vivo study and the photothermal effects and therapeutic efficacy of NPs were evaluated.Results:The DOX&IR780@PEG-PCL-SS NPs were synthesized using internal cross-linking strategy to increase the stability of nanoparticles. Nanoparticles can be ingested by tumor cells in a short time. The DOX&IR780@PEG-PCL-SS NPs have dual sensitivity to high levels of glutathione in bladder cancer cells and near-infrared laser irradiation. Glutathione triggers chemical structural changes of nanoparticles and preliminarily releases drugs, Near-infrared laser irradiation can promote the complete release of the drugs from the nanoparticles and induce a photothermal effect, leading to destroying the tumor cells. Given the excellent tumor-targeting ability and negligible toxicity to normal tissue, DOX&IR780@PEG-PCL-SS NPs can greatly increase the concentration of the anti-cancer drugs in tumor cells. The mice treated with DOX&IR780@PEG-PCL-SS NPs have a significant reduction in tumor volume. The DOX&IR780@PEG-PCL-SS NPs can be tracked by in vivo imaging system and have good tumor targeting ability, to facilitate our assessment during the experiment.Conclusion:A nanoparticle delivery system with dual sensitivity to glutathione and near-infrared laser irradiation was developed for delivering IR780 and DOX. Chemo-photothermal synergistic therapy of both primary bladder cancer and their metastases was achieved using this advanced delivery system.

Download Full-text