Today 70% of patients with advanced ovarian cancer will achieve clinically complete remission with front line treatments of carboplatin and paclitaxel, unfortunately a majority these patients are destined to relapse and eventually die of disease within 12-18 months due to a persistence of chemoresistant cells. Diagnostic techniques for ovarian cancer include normal exam, monitoring CA-125 level and CT-scans all capable of observing gross changes in disease progression but are less sensitive at quantitating the number or location of chemoresistant cells. Our overarching strategy addresses the major failures of the front line therapy and diagnostics by using multifunctional nanoemulsions to target, image, and enhance cytotoxicity to simultaneously eradicate chemosensitive and chemoresistant tumor cells. Extending our positive rodent studies combining targeting, imaging and therapeutic in a single vehicle, these proposed studies will focus on engineering multifunctional nanoemulsions capable of: 1) Targeting EGFR expressing cells which is found on majority of ovarian cancers;2) imaging disease regression or progression by delivering DPTA-Gd3+, an magnetic resonance imaging (MRI) contrast agent, directly to tumor cells;and 3) enhance the cytotoxicity of carboplatin by targeting but also by co-delivering the pro-apoptotic molecule C6-ceramide, shown to reestablish key apoptosis pathways to overcome chemoresistance. Preclinical studies will be carried out in human ovarian adenocarcinoma xenograft models in female nu/nu mice to identify key pharmacokinetics parameters, efficacy, and ability to image delivery efficiency and disease progression using MRI. Successful completion of these studies will guide Phase II studies to generate safety, pharmacokinetics, efficacy and scale-up manufacturing data to advance to clinical trials. Phase I outcomes will additionally encourage exploration of enhancing the targeted delivery of other chemotherapeutic drugs or other compounds that had not previously been evaluated clinically due to physical properties, bioavailability or toxicities. , ,
Public Health Relevance: An estimated 22,000 new cases in 2008 and approximately 15,000 deaths in the United States, epithelial ovarian cancer is the most lethal of gynecologic cancers, due to its propensity to spread into the upper abdomen and beyond. Frontline lead to clinically complete remission in over 70% of patients, however typically within 12-18 months those patients relapse due to chemoresistant cells. Diagnostic techniques for ovarian cancer include normal exam, monitoring CA-125 level and CT-scans all capable of observing gross changes in disease progression but are less sensitive at quantitating the number or location of chemoresistant cells. Our overarching strategy addresses the major failures of the front line therapy and diagnostics by using multifunctional nanoemulsions to target, image, and enhance cytotoxicity to simultaneously eradicate chemosensitive and chemoresistant tumor cells.
Thesaurus Terms: (Sp-4-2)-Diammine[1,1-Cyclobutanedicarboxylato(2--)-O,O']platinum;1,1-Cyclobutanedicarboxylic Acid Platinum Complex;Abdomen;Abdominal;Address;Adenocarcinoma Of The Ovary;Adverse Effects;Anzatax;Apoptosis;Apoptosis Pathway;Apoptotic;Asotax;Assay;Bioassay;Bioavailability;Biodistribution;Biologic Assays;Biologic Availability;Biological Assay;Biological Availability;Blood Plasma;Bristaxol;C(6)-Ceramide;C6-Ceramide;Ca-125;Ca-125 Antigen;Ca125;Cat Scan, X-Ray;Cat Scan;Cbdca;Ct X Ray;Ct Scan;Cancer Antigen 125;Cancer Model;Cancer Patient;Cancer Of The Ovary;Cancermodel;Cancers;Carbohydrate Antigen 125;Carboplatin;Carboplatino;Cell Death, Programmed;Cells;Ceramide (Lipids);Ceramides;Cessation Of Life;Charge;Cis-Diammine(Cyclobutane-1,1-Dicarboxylato)Platinum;Clinical Trials;Clinical Trials, Unspecified;Combined Modality Therapy;Computed Tomography;Computerized Axial Tomography (Computerized Tomography);Computerized Tomography, X-Ray;Contrast Agent;Contrast Drugs;Contrast Media;Data;Death;Diagnostic;Diagnostic Method;Diagnostic Procedure;Diagnostic Technique;Disease;Disease Progression;Disease Regression;Disease Remission;Disorder;Dose;Drug Formulations;Drug Kinetics;Drugs;Egfr;Emi Scan;Erbb Protein;Erbb1;Engineering;Engineerings;Epidermal Growth Factor Receptor;Epidermal Growth Factor Receptor Kinase;Epidermal Growth Factor Receptor Protein-Tyrosine Kinase;Epithelial Ovarian Cancer;Flr;Failure (Biologic Function);Female;Female Reproductive Cancer;Formulation;Formulations, Drug;Gadolinium;Gd Element;Goals;Gynecologic Cancer;Her1;Heterograft;Human;Human, General;Hydrogen Oxide;Image;In Vitro;In Complete Remission;Injection Of Therapeutic Agent;Injections;Lead;Location;Lytotoxicity;Mr Imaging;Mr Tomography;Mri;Magnetic Resonance Imaging;Magnetic Resonance Imaging Scan;Malignant Cell;Malignant Female Reproductive System Neoplasm;Malignant Gynecologic Neoplasm;Malignant Gynecologic Tumor;Malignant Neoplasms;Malignant Ovarian Neoplasm;Malignant Ovarian Tumor;Malignant Tumor;Malignant Tumor Of The Female Reproductive System;Malignant Tumor Of The Ovary;Malignant Neoplasm Of Ovary;Mammals, Mice;Mammals, Rodents;Man (Taxonomy);Man, Modern;Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance;Medication;Mice;Monitor;Morphology;Multimodal Therapy;Multimodal Treatment;Multimodality Treatment;Murine;Mus;N-Caproylsphingosine;N-Hexanoylsphingosine;Nmr Imaging;Nmr Tomography;Newly Diagnosed;Nuclear Magnetic Resonance Imaging;Oils;Outcome;Ovarian Adenocarcinoma;Ovarian Adenocarcinoma Not Otherwise Specified;Ovarian Tumor;Ovary Neoplasms;Paclitaxel;Paclitaxel (Taxol);Particle Size;Patients;Pb Element;Peptides;Pharmaceutic Preparations;Pharmaceutical Preparations;Pharmacokinetics;Phase;Physiologic Availability;Plasma;Platinum;Platinum Black;Position;Positioning Attribute;Praxel;Pt Element;Rmsn;Radiopaque Media;Receptor, Egf;Receptor, Tgf-Alpha;Receptor, Urogastrone;Receptors, Epidermal Growth Factor-Urogastrone;Regression;Relapse;Remission;Reticuloendothelial System, Serum, Plasma;Rodent;Rodentia;Rodentias;Safety;Serum, Plasma;Staging;Surface;Suspension Substance;Suspensions;Taxol;Taxol (Old Nsc);Taxol A;Taxol Konzentrat;Technology;Therapeutic;Time;Tomodensitometry;Tomography, Xray Computed;Toxic Effect;Toxicities;Transforming Growth Factor Alpha Receptor;Transplantation, Heterologous;Treatment Efficacy;Treatment Side Effects;Tumor Cell;Tumor Of The Ovary;United States;Water;X-Ray Computed Tomography;Xenograft;Xenograft Model;Xenograft Procedure;Xenotransplantation;Zeugmatography;Aqueous;Base;Bioavailability Of Drug;C-Erbb-1;C-Erbb-1 Protein;Cancer Cell;Catscan;Cis-Diammine(Cyclobutanedicarboxylato)Platinum Ii;Cis-Diammine(1,1-Cyclobutanedicarboxylato) Platinum(Ii);Clinical Investigation;Clinical Practice;Combination Therapy;Combined Modality Treatment;Combined Treatment;Complete Response;Computed Axial Tomography;Computerized Axial Tomography;Computerized Tomography;Cytotoxicity;Disease/Disorder;Drug/Agent;Erbb-1;Erbb-1 Proto-Oncogene Protein;Erbbl;Failure;Heavy Metal Pb;Heavy Metal Lead;Imaging;Improved;In Vivo;Intraperitoneal;Malignancy;Manufacturing Scale-Up;Mouse Model;Multimodality Therapy;Nano Emulsion;Nano Particle;Nanoemulsion;Nanoparticle;Neoplasm/Cancer;Neoplastic Cell;Novel;Ovarian Cancer;Ovarian Cancer, Adenocarcinoma;Ovarian Neoplasm;Particle;Phase 2 Study;Physical Property;Platinum, Diammine(1,1-Cyclobutanedicarboxylato(2-))-, (Sp-4-2);Preclinical Study;Proto-Oncogene Protein C-Erbb-1;Public Health Relevance;Receptor Binding;Side Effect;Site Targeted Delivery;Suspension;Targeted Delivery;Therapeutic Efficacy;Therapeutically Effective;Therapy Adverse Effect;Treatment Adverse Effect;Tumor;Uptake
