Combined Cancer Therapy with RF Ablation and Drug-Loaded Nanopreparations Our goal is to improve tumor destruction by rationally combining image-guided, minimally invasive imageguided radiofrequency (RF) thermal ablation with adjunctive nanotherapies. We propose to match the loaded agents within our nanopreparations to exploit key mechanisms generated by thermal ablation including cell stress and apoptosis, and more peripherally heat shock protein (HSP) production, as well as use nanodrug enhanced RF-induced hyperthermia to help overcome multidrug resistance. Accordingly, the current proposal will initially cover nanopreparations containing powerful proapoptotic agents such as paclitaxel (Aim 1), cell stress inducers such as GLA and BSO (Aim 2), and quercitin a known down-regulator of HSP (Aim 3). In general, we will adhere to a strategy that has proven successful for our translation of the paradigm of RF ablation combined with Doxil from idea through animal studies to clinical practice. For each proposed nanoagent, this step-wise approach will include in vivo: 1) characterization and optimization of the parameters most relevant to our system (i.e. adjuvant dosing, thermal dosing, interval timing of therapies, and the timing of maximal effect) in relevant animal models (R3230 rat mammary adenocarcinoma, and the MDR expressed and absent variants of M109 lung carcinoma, and Daoy medulloblastoma in mice);2) correlation of endpoints of tumor destruction, drug uptake, and thermal dosimetry with the proposed relevant mechanisms;and 3) comparison of the two primary endpoints coagulation diameter and animal survival among the different proposed adjuvant nanotherapies alone and in combination (Aim 5). We additionally propose loading of clinically relevant imaging markers that will enable determination of correlation between spatial distribution at MR imaging of the relevant nanopreparations and resultant tumor destruction (Aim 4). Overall, this comprehensive approach will enable us to identify appropriate nanoagents for combination with RF ablation anticipated future clinical trials particularly for lung, liver, breast, and MDR tumors.

Public Health Relevance

We will improve RF ablation, an image-based, method for treating tumors, by combining it with drugs delivered in special nanopreparations that complement RF heating. Such combination therapy will permit effective treatment of larger tumors;enable increased tumor destruction near vessels (important for many central lung and liver tumors);and provide ways to treat tumors that are resistant to multiple cancer drugs.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
5U54CA151881-04
Application #
8537852
Study Section
Special Emphasis Panel (ZCA1-GRB-S)
Project Start
Project End
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
4
Fiscal Year
2013
Total Cost
$385,569
Indirect Cost
Name
Northeastern University
Department
Type
DUNS #
001423631
City
Boston
State
MA
Country
United States
Zip Code
02115
Petrenko, Valery A; Gillespie, James W (2016) Paradigm shift in bacteriophage-mediated delivery of anticancer drugs: from targeted 'magic bullets' to self-navigated 'magic missiles'. Expert Opin Drug Deliv :1-12
Han, Lei; Liu, Pei; Petrenko, Valery A et al. (2016) A Label-Free Electrochemical Impedance Cytosensor Based on Specific Peptide-Fused Phage Selected from Landscape Phage Library. Sci Rep 6:22199
Velez, Erik; Goldberg, S Nahum; Kumar, Gaurav et al. (2016) Hepatic Thermal Ablation: Effect of Device and Heating Parameters on Local Tissue Reactions and Distant Tumor Growth. Radiology 281:782-792
Kitatani, K; Usui, T; Sriraman, S K et al. (2016) Ceramide limits phosphatidylinositol-3-kinase C2β-controlled cell motility in ovarian cancer: potential of ceramide as a metastasis-suppressor lipid. Oncogene 35:2801-12
Gillespie, James W; Wei, Lixia; Petrenko, Valery A (2016) Selection of Lung Cancer-Specific Landscape Phage for Targeted Drug Delivery. Comb Chem High Throughput Screen 19:412-22
Zhang, Yilin; Sriraman, Shravan Kumar; Kenny, Hilary A et al. (2016) Reversal of Chemoresistance in Ovarian Cancer by Co-Delivery of a P-Glycoprotein Inhibitor and Paclitaxel in a Liposomal Platform. Mol Cancer Ther 15:2282-2293
Moussa, Marwan; Goldberg, S Nahum; Kumar, Gaurav et al. (2016) Effect of thermal dose on heat shock protein expression after radio-frequency ablation with and without adjuvant nanoparticle chemotherapies. Int J Hyperthermia 32:829-841
Gross, Amanda L; Gillespie, James W; Petrenko, Valery A (2016) Promiscuous tumor targeting phage proteins. Protein Eng Des Sel 29:93-103
Su, Mei-Ju; Aldawsari, Hibah; Amiji, Mansoor (2016) Pancreatic Cancer Cell Exosome-Mediated Macrophage Reprogramming and the Role of MicroRNAs 155 and 125b2 Transfection using Nanoparticle Delivery Systems. Sci Rep 6:30110
Sriraman, Shravan Kumar; Salzano, Giusseppina; Sarisozen, Can et al. (2016) Anti-cancer activity of doxorubicin-loaded liposomes co-modified with transferrin and folic acid. Eur J Pharm Biopharm 105:40-9

Showing the most recent 10 out of 76 publications