Vascular disrupting agent induced aggregation of gold nanoparticles for photothermally enhanced tumor vascular disruption

Although vascular disrupting agents (VDAs) have been extensively implemented in current clinical tumor therapy, the notable adverse events caused by long-term dosing severely limit the therapeutic efficacy. To improve this therapy, we report a strategy for VDA-induced aggregation of gold nanoparticles to further destroy tumor vascular by photothermal effect. This strategy could effectively disrupt tumor vascular and cut off the nutrition supply after just one treatment. In the murine tumor model, this strategy results in notable tumor growth inhibition and gives rise to a 92.7% suppression of tumor growth. Besides, enhanced vascular damage could also prevent cancer cells from distant metastasis. Moreover, compared with clinical therapies, this strategy still exhibits preferable tumor suppression and metastasis inhibition ability. These results indicate that this strategy has great potential in tumor treatment and could effectively enhance tumor vascular damage and avoid the side effects caused by frequent administration.

Download Full-text

new bIologIcal model of moderate InhIbItIon of tumor and metastases growth wIth prolonged leukopenIa In mIce

Бюллетень Восточно-Сибирского научного центра Сибирского отделения Российской академии медицинских наук ◽

10.12737/23406 ◽

2016 ◽

Vol 1 (5) ◽

pp. 121-125

Author(s):

Зуева ◽

Elena Zueva ◽

Разина ◽

Tatyana Razina ◽

Ермакова ◽

...

Keyword(s):

Tumor Growth ◽

Lung Carcinoma ◽

Lewis Lung Carcinoma ◽

Tumor Therapy ◽

Biological Model ◽

Tumor Growth Inhibition ◽

Lewis Lung ◽

Inhibition Of Tumor Growth ◽

Toxic Manifestation ◽

Cyclophosphamide Dose

A new biological model of moderate inhibition of tumor growth and metastases with prolonged leukopenia on C57Bl/6 mice with the Lewis Lung Carcinoma was designed. The model was created by the injection of cyclophosphamide (dose 83.3mg/kg) on 6th, 12th, 18th days after tumor cells transplantation on animals. Experiment showed that 3-fold cyclo-phosphamide use leads to growth of primary tumor and metastases inhibition. Tumor growth inhibition was 34% on 21st day after cyclophosphamide inject. The number of metastases decreased by 4.7times (p<0,01). Metastatic area reduced. Metastasis frequency made 100%. In addition, the course of cyclophosphamide application caused inhibition of granulocytic and lymphoid hematopoiesis. The reducing the number of segmented neutrophils and lymphocytes was showed on the 3rd day after 1, 2 and 3 injections of cyclophosphamide. The model can be used to study the efficacy of drugs in tumor therapy and in correction of such toxic manifestation of chemotherapy as leukopenia.

Download Full-text

Anti-Tumor Activity of the Aurora a Inhibitor MLN8237 in Diffuse Large B-Cell Lymphoma Preclinical Models.

Blood ◽

10.1182/blood.v112.11.1592.1592 ◽

2008 ◽

Vol 112 (11) ◽

pp. 1592-1592 ◽

Cited By ~ 1

Author(s):

Jessica J Huck ◽

Mengkun Zhang ◽

Marc L Hyer ◽

Mark G Manfredi

Keyword(s):

Tumor Growth ◽

Growth Inhibition ◽

Tumor Model ◽

B Cell Lymphoma ◽

Tumor Growth Inhibition ◽

Aurora A ◽

Hct 116 ◽

Xenograft Models

Abstract Aurora A kinase is a serine/threonine protein kinase that is essential for normal transit of cells through mitosis. In many tumor types the Aurora A gene is amplified and/or the protein is over-expressed. The Aurora A small-molecule inhibitor MLN8237 demonstrated robust tumor growth inhibition in xenograft models of solid tumors grown subcutaneously (S.C.) in immunocompromised mice. Here we explored the antitumor activity of MLN8237 in models of diffuse large B-cell lymphoma (DLBCL) both in vitro and in vivo. In vivo three established DLBCL xenograft models (OCI-Ly7, OCI-Ly19, and WSU-DLCL2; all cells expressing luciferase) and a primary DLBCL tumor model PHTX-22-06 were tested using MLN8237 at different doses. Rituximab, an anti-CD20 monoclonal antibody that is active against CD20+ malignant B cells and is a standard of care agent was used for comparison. Using these model systems, tumor cells were injected either I.V. (to evaluate disseminated disease), or S.C. in severe combined immunodeficient mice (SCID). Animals were dosed orally for 21 days with MLN8237 (QD or BID) at various doses, or Rituximab dosed at 10mg/kg IV (once/week) and tumor growth inhibition was monitored using either bioluminescent imaging for the disseminated models or vernier calipers for the S.C. models. Tumor growth inhibition by MLN8237 was dose dependent with 20 mg/kg bid being the most efficacious dose (TGI>100% in both disseminated OCI-Ly19 and WSU models). All animals in the OCI-Ly19 disseminated model 20 mg/kg BID treatment group demonstrated regressions and remained disease free until the end of the study, day 65. In this study the Rituximab treated animals were euthanized on day 31 due to a high level of tumor burden. In the primary tumor model, PHTX-22-06, MLN8237 dosed at 20 mg/kg BID was also the most efficacious with a TGI of 95%. Moreover, tumor growth inhibition was durable as determined by prolonged tumor growth delay (>50 days). Significant efficacy was achieved in all models tested, whether grown as disseminated or subcutaneous models. A noted increase in durability of response was observed with MLN8237 treatment when compared with previous data from solid tumor models. In vitro, MLN8237 treatment increased levels of apoptosis in the OCI-Ly19 cells in comparison to the solid tumor cell line HCT-116 (colon). Greater Annexin V positive cells and greater cleaved PARP and Caspase-3 signals were detected in the MLN8237 treated OCI-Ly19 cells when compared to HCT-116 cells. The demonstration of robust and durable anti-tumor activity in preclinical models treated with MLN8237 provides the basis for its clinical evaluation as a treatment option for DLBCL. MLN8237 is currently in multiple Phase I clinical trials.

Download Full-text

Combination of TLR9 agonists EnanDIM with checkpoint inhibitors for cancer immunotherapy.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.7_suppl.134 ◽

2017 ◽

Vol 35 (7_suppl) ◽

pp. 134-134

Author(s):

Manuel Schmidt ◽

Kerstin Kapp ◽

Detlef Oswald ◽

Burghardt Wittig ◽

Barbara Volz

Keyword(s):

Immune System ◽

Tumor Growth ◽

Colon Carcinoma ◽

Mononuclear Cells ◽

Checkpoint Inhibitors ◽

Tumor Model ◽

Tumor Growth Inhibition ◽

Mouse Tumor ◽

New Family ◽

Ifn Alpha

134 Background: TLR9 agonists have shown anti-tumor effects by modulating the innate and adaptive immune system. Ongoing clinical studies support the use of TLR9 agonists for immunotherapeutic approaches. The new family of TLR9 agonists, EnanDIM, consists of linear single-stranded ODN synthesized using L-deoxyribonucleotides (natural enantiomers of D-deoxyribonucleotides) at their 3’-ends to prevent degradation. Therefore, EnanDIM does not own the off-target effects of PTO-modified CpG-ODN. Methods: EnanDIM with varying nucleotid sequences were compared for IFN-alpha response from human peripheral blood mononuclear cells and those molecules inducing the stronges response were selected. A maximum feasible dose (MFD) approach was employed to evaluate their acute toxicity and immunomodulatory properties. In addition, a combinatory approach with aPD-1 was evaluated in an syngeneic colon carcinoma CT26 mouse tumor model. Results: EnanDIM581 and EnanDIM532 were selected due to their pronounced activation of the IFN-alpha pathway in vitro. Safety assessments throughout and a gross necropsy at the end of the study revealed no signs of toxicity despite extremely high doses (300 - 1700 mg/kg). Dose-dependent increase of IP-10 levels in serum was observed between 6 and 24 hours after injection. In the colon carcinoma CT26 model subcutaneous injection of EnanDIM532 and intraperitoneal injection of aPD-1 had a moderate effect on the tumor growth when used in monotherapy (28.3% and 57.0% tumor growth inhibition, TGI). Notably, a combination of EnanDIM532 and aPD-1 further reduced tumor growth (74.7% TGI) and thus prolonged survival of the mice. Conclusions: In conclusion, EnanDIM, a new family of TLR9 agonists and immune surveillance reactivators (ISR), broadly activates the immune system, shows no toxicity in an MFD study and enhances the anti-tumor effects of the aPD-1 checkpoint inhibitor in a pilot study of a murine colon carcinoma tumor model. These data show the promising potential of EnanDIM not only for monotherapeutic but also combinatory approaches.

Download Full-text

Methotrexate Conjugated to Gold Nanoparticles Inhibits Tumor Growth in a Syngeneic Lung Tumor Model

Molecular Pharmaceutics ◽

10.1021/mp060132k ◽

2007 ◽

Vol 4 (5) ◽

pp. 713-722 ◽

Cited By ~ 206

Author(s):

Yu-Hung Chen ◽

Chiau-Yuang Tsai ◽

Pon-Yu Huang ◽

Meng-Ya Chang ◽

Pai-Chiao Cheng ◽

...

Keyword(s):

Gold Nanoparticles ◽

Tumor Growth ◽

Lung Tumor ◽

Tumor Model

Download Full-text

Penetration and Silencing Activity of VEGF Dicer Substrate siRNA Vectorized by Chitosan Nanoparticles in Monolayer Culture and a Solid Tumor ModelIn Vitrofor Potential Application in Tumor Therapy

Journal of Nanomaterials ◽

10.1155/2016/7201204 ◽

2016 ◽

Vol 2016 ◽

pp. 1-16 ◽

Cited By ~ 3

Author(s):

Maria Abdul Ghafoor Raja ◽

Haliza Katas ◽

Zariyantey Abd Hamid

Keyword(s):

Solid Tumor ◽

Monolayer Culture ◽

Tumor Therapy ◽

Chitosan Nanoparticles ◽

Tumor Model ◽

Tumor Growth Inhibition ◽

Knock Down ◽

Human Solid Tumors ◽

Solid Tumor Model

Penetration and distribution of drug through the avascular regions of human solid tumors after extravasation are crucial concerns for antitumor efficacy. To address this issue, anin vitrosolid tumor model of multicellular layers (MCLs) of human colorectal cancer cells (DLD-1) was established. In an attempt to deliver Dicer substrate small interfering RNA (DsiRNA), chitosan (CS) nanoparticles have been developed for targeting vascular endothelial growth factor (VEGF) gene for tumor growth inhibition. The DsiRNA-CS nanoparticles prepared by ionic gelation method had provided maximal protection of DsiRNA in full human serum up to 48 h incubation. RT-PCR studies revealed significant concentration- and time-dependent knock-down ofVEGFmRNA and its product due to uniform penetration of DsiRNA-CS nanoparticles throughout MCLs. Taken together, this study also demonstrated that DsiRNA-CS nanoparticles could effectively knock downVEGFgene as therapeutic target in monolayer culture or in solid tumor model for potential treatment of human colorectal carcinoma.

Download Full-text

IFN-β-Dependent Inhibition of Tumor Growth by the Vascular Disrupting Agent 5,6-Dimethylxanthenone-4-Acetic Acid (DMXAA)

Journal of Interferon & Cytokine Research ◽

10.1089/jir.2007.0992 ◽

2008 ◽

Vol 28 (3) ◽

pp. 133-139 ◽

Cited By ~ 20

Author(s):

Zachary J. Roberts ◽

Lai-Ming Ching ◽

Stefanie N. Vogel

Keyword(s):

Acetic Acid ◽

Tumor Growth ◽

Vascular Disrupting Agent ◽

Dependent Inhibition ◽

Inhibition Of Tumor Growth ◽

Vascular Disrupting

Download Full-text

Antitumor efficiency of contact radiotherapy in combination with a chlorin-based photosensitizer in experiment

Biomedical Photonics ◽

10.24931/2413-9432-2021-10-2-25-33 ◽

2021 ◽

Vol 10 (2) ◽

pp. 25-33

Author(s):

D. A. Tzerkovsky ◽

Ya. L. Protopovich ◽

D. I. Kozlovsky ◽

V. A. Suslova

Keyword(s):

Radiation Therapy ◽

Tumor Growth ◽

Growth Inhibition ◽

Tumor Model ◽

Growth Patterns ◽

Antitumor Efficacy ◽

Laboratory Animals ◽

Tumor Growth Inhibition ◽

Histological Structure ◽

Complete Tumor

Authors have studied the antitumor efficacy of contact radiation therapy (CRT) in combination with a chlorin-based photosensitizer (PS) in an experiment on laboratory animals with transplanted tumors. The experimental study was performed in 50 white outbred rats weighing 250±50 g. Subcutaneously transplanted Pliss lymphosarcoma (PLS) and alveolar liver cancer RS1 (RS1) were used as tumor models. Chlorinbased PS photolon (RUE «Belmedpreparaty», Republic Belarus) was injected intravenously at a dose of 2.5 mg/kg. The radiation sessions were carried out 2.5–4 hours (depending on the tumor model) after the administration of the PS using the device «microSelectron HDR V3 Digital» («Nucletron», Netherlands) with a 192-Ir radiation source in single focal doses 5 and 10 Gy. All laboratory animals (for PLS and RS1) were subdivided into 5 groups of 5 animals each: intact control, CRT 5 Gy, CRT 10 Gy, PS + CRT 5 Gy, PS + CRT 10 Gy. For the PLS tumor model – on the 14th day from the beginning of the experiment Vav. in groups were 26.31±5.81; 22.45±6.97; 18.99±4.86; 10.75±5.18 and 28.06±2.85 cm3, respectively (p˂0.05). The coefficients of tumor growth inhibition in the experimental groups were 14.67%, 27.82%, 59.14% and 6.65%, respectively. The frequency of complete tumor regressions 60 days after the start of the experiment was 0%, 20%, 20%, 60%, and 20%, respectively. On RS1 tumor model – on the 14th day from the beginning of the experiment Vav. in groups were 4.48±1.03; 0.80±0.21; 0.29±0.09; 0.19±0.07 and 0.32±0.08 cm3, respectively (p=0.009). The coefficients of tumor growth inhibition in the experimental groups were 82.14%, 93.53%, 95.76% and 92.86%, respectively. The frequency of complete tumor regressions 60 days after the start of the experiment was 0%, 0%, 20%, 0%, and 0%, respectively. Systemic administration of chlorin-based PS before the CRT session increases the antitumor efficacy of radiation therapy in animals with transplantable tumors of different histological structure and growth patterns. The data obtained indicate that further studies of the radiosensitizing properties of PS are promising.

Download Full-text

Abstract 677: Effects of the vascular disrupting agent ASA404 on tumor growth of gastric cancer in an experimental model

10.1158/1538-7445.am2011-677 ◽

2011 ◽

Author(s):

Christian Moser ◽

Sven A. Lang ◽

Ernst M. Jung ◽

Karin Pfister ◽

Edward K. Geissler ◽

...

Keyword(s):

Gastric Cancer ◽

Tumor Growth ◽

Experimental Model ◽

Vascular Disrupting Agent ◽

Vascular Disrupting

Download Full-text

Effects of ASA404, a vascular disrupting agent, on tumor growth of gastric cancer in an experimental model.

Journal of Clinical Oncology ◽

10.1200/jco.2011.29.4_suppl.48 ◽

2011 ◽

Vol 29 (4_suppl) ◽

pp. 48-48 ◽

Cited By ~ 1

Author(s):

S. A. Lang ◽

C. Moser ◽

E. M. Jung ◽

K. Pfister ◽

E. K. Geissler ◽

...

Keyword(s):

Gastric Cancer ◽

Tumor Growth ◽

Experimental Model ◽

Vascular System ◽

Tumor Vasculature ◽

Gastric Cancer Cells ◽

Vascular Disrupting Agent ◽

Vascular Disrupting

48 Background: A functional vascular system is essential for growth of solid malignancies including gastric cancer. For establishment and maintenance of such a vascular system endothelial cells (ECs) and pericytes (e.g. vascular smooth muscle cells, VSMC) are required. We hypothesized that targeting tumor vasculature with the vascular disrupting agent (VDA) ASA404 (Novartis Oncology) reduces tumor growth in a model of gastric cancer. Methods: Gastric cancer (GC) cell lines, ECs and VSMCs were used for experiments. Effects of ASA404 on growth of GC, EC and VSMC were assessed by MTT assays. Impact of ASA404 (20 mg/kg on day 1, 5, 9) in combination with paclitaxel (10 mg/kg on day 1 and 7) on tumor growth was assessed in a subcutaneous tumor model. Treatment was started when tumors reached a size of approximately 200 mm3. Tumors were measured and harvested on day 23 for IHC analyses. Effect of ASA404 on blood perfusion of tumors during therapy was monitored by contrast-enhanced ultrasound (CEUS). Results: In vitro ASA404 impaired growth of ECs and VSMCs upon stimulation with condition media from gastric cancer cells. No direct effect on tumor cells was observed. In vivo, treatment with ASA404 led to marked decrease of tumor perfusion and an increase of necrosis as determined by CEUS. Furthermore, combination of ASA404 with paclitaxel showed significant reduction of tumor growth compared to controls (p < 0.05). In addition, tumor vascularisation and tumor cell proliferation were significantly reduced as determined by CD31-positive vessel area and BrdU-positive cells (p < 0.05). Conclusions: Combination of the VDA ASA404 with paclitaxel impairs tumor growth and perfusion of gastric cancer in an experimental model. Hence, targeting tumor vasculature with ASA404 appears to be a promising strategy for therapy of gastric cancer. No significant financial relationships to disclose.

Download Full-text