Thyrointegrin αvβ3 nano targeted delivery of chemotherapy into solid tumors and its microenvironment.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e14661-e14661
Author(s):  
Dhruba J. Bharali ◽  
Thangirala Institute Sudha ◽  
Kavitha Godugu ◽  
Noureldien H.E Darwish ◽  
Paul Joseph Davis ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Targeted Delivery ◽  
Chemotherapeutic Agent ◽  
Urinary Bladder Cancer ◽  
Chemotherapeutic Agents ◽  
Cell Surface Receptor ◽  
Human Pancreatic Cancer ◽  
Specific Cell ◽  
Αvβ3 Integrin ◽  
Animal Group

e14661 Background: Cancer cells and rapidly dividing endothelial cells relevant to tumors primarily express the αvβ3 integrin. Conjugation of tetraiodothyroacetic acid (tetrac) as diamino-tetrac to a poly (lactic-co-glycolic acid) (PLGA) polymer for the formation of Nano DAT was used to target a specific cell surface receptor on the αvβ3 integrin. PLGA prohibits cell entry and the nano shell could be loaded with a generic cancer chemotherapeutic. Without a payload, Nano DAT has anticancer and anti-angiogenesis properties. Methods: Xenografts of human urinary bladder cancer (263JBV) cells, human breast cancer (SUM149PT) cells, and human pancreatic cancer (SUIT-2) cells were established. Tumor growth and tumor content of cisplatin (263JBV xenografts), doxorubicin (SUM149PT xenografts), or of paclitaxel (SUIT-2 xenografts) were compared in the following daily treatment animal arms of cohorts for 3 weeks: (1) controls, (2) void PLGA Nanoparticle (NPs), (3) chemotherapeutic agent (cisplatin 1 mg/kg, doxorubicin 1 mg/kg, or paclitaxel 0.3 mg/kg), (4) Nano DAT 0.3 mg/kg, and (5) chemotherapeutic agent encapsulated into PLGA NPs and into Nano DAT. Results: Tumors in animals treated with Nano DAT bearing a payload of cisplatin, paclitaxel, or doxorubicin were associated with decreased tumor weight by 50%-60% (P < 0.01) with > 90% loss of cancer cell viability. Mean chemotherapeutic agents content of tumors (ng/gm of tissue) was 5-fold that of tumors from animals treated with chemotherapy, alone, and 3-fold that of tumors exposed to chemotherapy encapsulated into PLGA NPs, measured with an established LC/MS/MS method. Animals receiving cisplatin, alone, developed neurotoxicity (inability to use the hind limbs) in comparison to an animal group treated with Nano DAT bearing a payload of cisplatin, and was confirmed histopathologically. Conclusions: The payload capacity of Nano DAT for cancer chemotherapeutic agents and tumor-specific delivery of cancer chemotherapeutic agents significantly increases bladder, breast and pancreatic cancer content of, respectively, cisplatin and paclitaxel.

scholarly journals Thermal cycling-hyperthermia in combination with polyphenols, epigallocatechin gallate and chlorogenic acid, exerts synergistic anticancer effect against human pancreatic cancer PANC-1 cells

2019 ◽  
Author(s):  
Chueh-Hsuan Lu ◽  
Wei-Ting Chen ◽  
Chih-Hsiung Hsieh ◽  
Yu-Yi Kuo ◽  
Chih-Yu Chao
Keyword(s):  
Pancreatic Cancer ◽  
Thermal Cycling ◽  
Chlorogenic Acid ◽  
Epigallocatechin Gallate ◽  
Chemotherapeutic Agents ◽  
Human Pancreatic Cancer ◽  
Synergistic Activity ◽  
Anticancer Effect ◽  
M Phase ◽  
Novel Strategy

AbstractHyperthermia (HT) has shown feasibility and potency as an anticancer therapy. Administration of HT in the chemotherapy has previously enhanced the cytotoxicity of drugs against pancreatic cancer. However, the drugs used when conducting these studies are substantially conventional chemotherapeutic agents that may cause unwanted side effects. Additionally, the thermal dosage in the treatment of cancer cells could also probably harm the healthy cells. The purpose of this work was to investigate the potential of the two natural polyphenolic compounds, epigallocatechin gallate (EGCG) and chlorogenic acid (CGA), as heat synergizers in the thermal treatment of the PANC-1 cells. Furthermore, we have introduced a novel strategy entitled the thermal cycling-hyperthermia (TC-HT) that is capable of providing a maximum synergy and minimal side effect with the anticancer compounds. Our results demonstrate that the combination of the TC-HT and the CGA or EGCG markedly exerts the anticancer effect against the PANC-1 cells, while none of the single treatment induced such changes. The synergistic activity was attributed to the cell cycle arrest at the G2/M phase and the induction of the ROS-dependent mitochondria-mediated apoptosis. These findings not only represent the first thermal synergistic study of natural compounds in the treatment of pancreatic cancer, but also highlight the potential application of the TC-HT as an alternative strategy in anticancer treatment.

scholarly journals Gemcitabine Induces Microvesicle Particle Release in a Platelet-Activating Factor-Receptor-Dependent Manner via Modulation of the MAPK Pathway in Pancreatic Cancer Cells

2018 ◽  
Vol 20 (1) ◽  
pp. 32 ◽  
Author(s):  
Anita Thyagarajan ◽  
Sayali Kadam ◽  
Langni Liu ◽  
Lisa Kelly ◽  
Christine Rapp ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cancer Cells ◽  
Mapk Pathway ◽  
Platelet Activating Factor ◽  
Chemotherapeutic Agents ◽  
Acid Sphingomyelinase ◽  
Mitogen Activated Protein Kinase ◽  
Human Pancreatic Cancer ◽  
Dependent Manner ◽  
Pancreatic Cancer Cells

Studies, including ours, have shown that pro-oxidative stressors, such as chemotherapeutic agents, generate oxidized lipids with agonistic platelet-activating factor (PAF) activity. Importantly, recent reports have implicated that these PAF-agonists are transported extracellularly via microvesicle particles (MVPs). While the role of PAF-receptor (PAF-R) has been implicated in mediating chemotherapy effects, its significance in chemotherapy-mediated MVP release in pancreatic cancer has not been studied. The current studies determined the functional significance of PAF-R in gemcitabine chemotherapy-mediated MVP release in human pancreatic cancer cells. Using PAF-R-expressing (PANC-1) and PAF-R-deficient (Hs766T) cells, we demonstrate that gemcitabine induces MVP release in a PAF-R-dependent manner. Blocking of PAF-R via PAF-R antagonist or inhibition of MVP generation via inhibitor of acid sphingomyelinase (aSMase) enzyme, significantly attenuated gemcitabine-mediated MVP release from PANC-1 cells, however, exerted no effects in Hs766T cells. Notably, MVPs from gemcitabine-treated PANC-1 cells, contained a measurable amount of PAF-agonists. Mechanistically, pretreatment with ERK1/2 or p38 inhibitors significantly abrogated gemcitabine-mediated MVP release, indicating the involvement of mitogen-activated protein kinase (MAPK) pathway in PAF-R-dependent gemcitabine-mediated MVP release. These findings demonstrate the significance of PAF-R in gemcitabine-mediated MVP release, as well as the rationale of evaluating PAF-R targeting agents with gemcitabine against pancreatic cancer.

scholarly journals Anti-Tumor Effects of MAPK-Dependent Tumor-Selective Oncolytic Vaccinia Virus Armed with CD/UPRT against Pancreatic Ductal Adenocarcinoma in Mice

Cells ◽  
2021 ◽  
Vol 10 (5) ◽  
pp. 985
Author(s):  
Hajime Kurosaki ◽  
Motomu Nakatake ◽  
Teruhisa Sakamoto ◽  
Nozomi Kuwano ◽  
Masato Yamane ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Vaccinia Virus ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Fusion Gene ◽  
Mapk Pathway ◽  
Chemotherapeutic Agents ◽  
Mitogen Activated Protein Kinase ◽  
Human Pancreatic Cancer ◽  
Ductal Adenocarcinoma ◽  
Antitumor Effects

Engineered vaccinia virus serves as an oncolytic virus for cancer virotherapy. We evaluated the oncolytic characteristics of VGF- and O1-deleted recombinant mitogen-activated protein kinase (MAPK)-dependent vaccinia virus (MDRVV). We found that compared with viruses with the deletion of either gene alone, MDRVV is more attenuated in normal cells and can replicate in cancer cells that exhibit constitutive ERK1/2 activation in the MAPK pathway. We armed MDRVV with a bifunctional fusion gene encoding cytosine deaminase and uracil phosphoribosyltransferase (CD/UPRT), which converts 5-fluorocytosine (5-FC) into chemotherapeutic agents, and evaluated its oncolytic activity alone or in combination with 5-FC in human pancreatic cancer cell lines, tumor mouse models of peritoneal dissemination and liver metastasis, and ex vivo-infected live pancreatic cancer patient-derived tissues. CD/UPRT-armed MDRVV alone could efficiently eliminate pancreatic cancers, and its antitumor effects were partially enhanced in combination with 5-FC in vitro and in vivo. Moreover, the replication of MDRVV was detected in tumor cells of patient-derived, surgically resected tissues, which showed enlarged nuclei and high expression of pERK1/2 and Ki-67, and not in stromal cells. Our findings suggest that systemic injections of CD/UPRT-armed MDRVV alone or in combination with 5-FC are promising therapeutic strategies for pancreatic ductal adenocarcinoma.

scholarly journals Two Laser Treatments Can Improve Tumor Ablation Efficiency of Chemophototherapy

Pharmaceutics ◽  
2021 ◽  
Vol 13 (12) ◽  
pp. 2183
Author(s):  
Sanjana Ghosh ◽  
Jonathan F. Lovell
Keyword(s):  
Pancreatic Cancer ◽  
Laser Treatment ◽  
Drug Administration ◽  
Chemotherapeutic Agents ◽  
Tumor Ablation ◽  
Human Pancreatic Cancer ◽  
Mouse Tumor ◽  
Ablation Efficiency ◽  
Laser Treatments ◽  
Low Passage

Chemophototherapy is an emerging tumor ablation modality that can improve local delivery of chemotherapeutic agents. Long circulating doxorubicin (Dox) in porphyrin-phospholipid (PoP) liposomes (LC-Dox-PoP) has previously been developed as an effective chemophototherapy agent. In the present study, we observed that in mice, LC-Dox-PoP showed enhanced accumulation in human pancreatic tumor xenografts even with suboptimal light doses, as assessed by fluorometric analysis of tissue homogenates and microscopic imaging of Dox and PoP in tumor slices. A second laser treatment, at a time point in which tumors had greater drug accumulation as a result of the first laser treatment, induced potent tumor ablation. Efficacy studies were carried out in two human pancreatic cancer subcutaneous mouse tumor models; MIA PaCa-2 or low-passage patient derived pancreatic cancer xenografts. A single treatment of 3 mg/kg LC-Dox-PoP and an initial 150 J/cm2 laser treatment 1 h after drug administration, followed by second laser treatment of 50 J/cm2 8 h after drug administration, was more effective than a single laser treatment of 200 J/cm2 at either of those time points. Thus, this study presents proof-of-principle and rationale for using two discrete laser treatments to enhance the efficacy of chemophototherapy.

Enhancing the Therapeutic Efficacy of Bortezomib in Cancer Therapy Using Polymeric Nanostructures

2020 ◽  
Vol 25 (46) ◽  
pp. 4883-4892 ◽  
Author(s):  
Mitra Korani ◽  
Shahla Korani ◽  
Elham Zendehdel ◽  
Amin Reza Nikpoor ◽  
Mahmoud Reza Jaafari ◽  
...  
Keyword(s):  
Targeted Delivery ◽  
Therapeutic Option ◽  
Nuclear Factor Κb ◽  
Chemotherapeutic Agents ◽  
26S Proteasome ◽  
Reversible Inhibitor ◽  
Pharmacokinetic Parameters ◽  
Nanoparticle Delivery ◽  
High Doses ◽  
Nfκb Pathway

: Bortezomib (VELCADE®) is a boronate peptide and first-in-class proteasome inhibitor serving an important role in degenerating several intracellular proteins. It is a reversible inhibitor of the 26S proteasome, with antitumor activity and antiproliferative properties. This agent principally exerts its antineoplastic effects by inhibiting key players in the nuclear factor κB (NFκB) pathway involved in cell proliferation, apoptosis, and angiogenesis. This medication is used in the management of multiple myeloma. However, more recently, it has been used as a therapeutic option for mantle cell lymphoma. While promising, bortezomib has limited clinical applications due to its adverse effects (e.g., hematotoxicity and peripheral neuropathy) and low effectiveness in solid tumors resulting from its poor penetration into such masses and suboptimal pharmacokinetic parameters. Other limitations to bortezomib include its low chemical stability and bioavailability, which can be overcome by using nanoparticles for its delivery. Nanoparticle delivery systems can facilitate the targeted delivery of chemotherapeutic agents in high doses to the target site, while sparing healthy tissues. Therefore, this drug delivery system has provided a solution to circumvent the limitations faced with the delivery of traditional cancer chemotherapeutic agents. Our aim in this review was to describe polymer-based nanocarriers that can be used for the delivery of bortezomib in cancer chemotherapy.

In Vitro and In Vivo Antitumor Efficacy of Docetaxel and Sorafenib Combination in Human Pancreatic Cancer Cells

2010 ◽  
Vol 999 (999) ◽  
pp. 1-11
Author(s):  
P. Ulivi ◽  
C. Arienti ◽  
W. Zoli ◽  
M. Scarsella ◽  
S. Carloni ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cancer Cells ◽  
Antitumor Efficacy ◽  
Human Pancreatic Cancer ◽  
Pancreatic Cancer Cells
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