SBIR-STTR Award

This Phase I proposal details the rationale and the research plan for the synthesis and characterization of targeted, backbone degradable, long-circulating polymer conjugates containing two anticancer drugs per macromolecule. The polymeric carrier will be composed of alternating N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer segments (blocks) and enzymatically degradable oligopeptide sequences. Each construct will contain multiple copies of two anticancer drugs (paclitaxel and gemcitabine) and of Fab'fragment of the OV-TL16 antibody (complementary to OA-3 antigen expressed on the majority of human ovarian carcinomas). The combination of FDA approved anticancer drugs, paclitaxel and gemcitabine, is one of novel combinations evaluated in the clinics. Attachment of both drugs to the Fab'fragment-targeted, long-circulating (high molecular weight) backbone degradable HPMA copolymer carrier will result in enhanced and simultaneous delivery of both drugs to cancer cells. The combination of active targeting, due to biorecognition of the Fab'fragments, and of passive targeting, due to the EPR (enhanced permeability and retention) effect, will result in augmented efficacy and minimal adverse effects, thus improving the usefulness of cancer therapy. The specific aims of the proposal are three-fold: A) Design, synthesis, and characterization of Fab'fragment- targeted HPMA copolymer-paclitaxel/gemcitabine conjugates;optimization of the structure based on feedback from biological evaluation. B) Evaluation of the conjugates on human ovarian cancer cells in vitro: internalization and subcellular fate, stability and enzymatically catalyzed drug release, and cytotoxicity. C) Therapeutic efficacy of polymer-drug conjugates on a human ovarian carcinoma xenograft model in nude mice. By completion of the Phase I studies TheraTarget will have established the feasibility of synthesis and characterization of the HPMA copolymer-drug conjugates, evaluated their activity in vitro and in vivo, and selected the leading conjugate for Phase II evaluation. The ultimate goal of the project is the development of an effective and marketable polymer drug delivery system capable of significantly improving the survival time of ovarian cancer patients.

Public Health Relevance:
This Phase I proposal details the rationale and the research plan for the synthesis and characterization of backbone degradable, long-circulating polymer conjugates containing two anticancer drugs per macromolecule. The simultaneous delivery of two drugs to ovarian cancer cells will result in enhanced efficacy and minimal adverse effects, thus improving the usefulness of cancer therapy.

Thesaurus Terms:
1-(2-Oxo-4-Amino-1,2-Dihydropyrimidin-1-Yl)-2-Deoxy-2,2-Difluororibose;2',2'-Dfdc;2',2'-Difluoro-2'-Deoxycytidine;2',2'-Difluorodeoxycytidine;2'-Deoxy-2'-Difluorocytidine;2'deoxy-2',2'-Difluorocytidine;2,2 Difluorodexoycytidine;Atgn;Adverse Effects;Anti-Cancer Agents;Antibodies;Antigen Binding Fragment;Antigens;Antineoplastic Agents;Antineoplastic Drugs;Antineoplastics;Anzatax;Asotax;Athymic Mice;Athymic Nude Mouse;Binding;Binding (Molecular Function);Biological Feedback;Bristaxol;Cancer Drug;Cancer Patient;Cancer Treatment;Clinic;Development;Difluorodeoxycytidine;Drug Carriers;Drug Delivery;Drug Delivery Systems;Drug Targeting;Drugs;Evaluation;Fda Approved;Fab Fragments;Fab Immunoglobulins;Generations;Goals;Heterograft;Heterologous Transplantation;Human;Immunoglobulin, F(Ab) Fragment;In Vitro;Lytotoxicity;Malignant Cell;Malignant Neoplasm Therapy;Malignant Neoplasm Treatment;Malignant Ovarian Neoplasm;Malignant Ovarian Tumor;Malignant Tumor Of The Ovary;Malignant Neoplasm Of Ovary;Man (Taxonomy);Medication;Modern Man;Molecular Interaction;Molecular Weight;Neoplastic Disease Chemotherapeutic Agents;Nude Mice;Oligopeptides;Ovarian Carcinoma;Ovary Cancer;Ovary Carcinoma;Paclitaxel;Paclitaxel (Taxol);Permeability;Pharmaceutic Preparations;Pharmaceutical Preparations;Phase;Phase I Study;Polymers;Praxel;Reaction;Research;Sttr;Small Business Technology Transfer Research;Spinal Column;Spine;Structure;Taxol;Taxol (Old Nsc);Taxol A;Taxol Konzentrat;Testing;Therapeutic;Time;Treatment Efficacy;Treatment Side Effects;Tumor-Specific Treatment Agents;Vertebral Column;Xenograft;Xenograft Model;Xenograft Procedure;Xenotransplantation;Anti-Cancer Therapeutic;Anticancer Activity;Anticancer Agent;Anticancer Drug;Anticancer Therapeutic;Anticancer Therapy;Backbone;Base;Biodegradable Polymer;Bioresorbable Polymer;Cancer Cell;Cancer Therapy;Copolymer;Cytotoxicity;Dfdc;Dfdcyd;Degradable Polymer;Design;Designing;Developmental;Drug/Agent;Gemcitabine;Immunogen;Improved;In Vitro Assay;In Vitro Activity;In Vivo;Indexing;Intervention Efficacy;Macromolecule;Methacrylamide;Mouse Model;Nano Medicine;Nanomedicine;Novel;Ovarian Cancer;Phase 1 Study;Polymerization;Side Effect;Site Targeted Delivery;Synergism;Targeted Delivery;Therapeutic Efficacy;Therapeutically Effective;Therapy Adverse Effect;Therapy Efficacy;Treatment Adverse Effect;Tumor Xenograft

The purpose of this Phase II STTR project is to develop a polymeric system for the combination delivery of two antineoplastic agents, gemcitabine and paclitaxel. Based on the successful results of the STTR Phase I award, this Phase II proposal details the rationale and research plan for the synthesis and evaluation of in vivo efficacy of two novel macromolecular therapeutics with diverse and complementary mode of action for the treatment of ovarian carcinoma. Their design is based on new, innovative long-circulating backbone degradable N-(2- hydroxypropyl)methacrylamide (HPMA) copolymer - drug conjugates. The polymeric carrier will be composed of alternating HPMA copolymer segments (blocks) and enzymatically degradable oligopeptide sequences. Each construct will contain multiple copies of either gemcitabine or paclitaxel. The drugs are attached to the backbone via a lysosomally degradable spacer that will allow intracellular release and bioactivity. The choice of drugs bodes well for the success of the project. Gemcitabine is a synthetic nucleoside analog of cytidine. Its triphosphate metabolite is incorporated into DNA, thereby stopping cell division. Gemcitabine has demonstrated activity in several ovarian cancer models and has been approved by FDA for combination therapy of ovarian cancer. Paclitaxel is a mitotic inhibitor, which acts by stabilizing microtubules, thereby inhibiting their breakdown during cellular division It is currently indicated as first-line and subsequent therapy for the treatment of advanced stages of ovarian cancer. The long circulating time of the new, innovative backbone degradable carriers will result in augmented tumor accumulation due to the EPR (enhanced permeability and retention) effect. In addition, the combination of two polymer-drug conjugates with diverse mechanisms of action will result in enhanced efficacy of ovarian cancer treatment and minimal adverse effects. The specific aims of the proposal are three-fold: a) To scale up of the synthesis and to characterize backbone degradable HPMA copolymer-drug (gemcitabine and paclitaxel) conjugates containing enzymatically degradable sequences in the backbone and in side chains; b) To establish the maximum tolerated dose (MTD) as well as the acute toxicity of the conjugates and their combination in vivo; and c) To evaluate the biodistribution, clearance, anticancer efficacy and dose escalation studies of the conjugates in vivo. The ultimate goal of this project is to develop an effective and marketable drug combination with a novel drug delivery system for the treatment of ovarian cancer where the drugs are localized at the site of the tumor, adverse effects of chemotherapy are minimized and efficacy maximized.

Thesaurus Terms:
Acute;Adverse Effects;Animal Model;Antimitotic Agents;Antineoplastic Agents;Award;Base;Biocompatible;Biodegradable Polymer;Biodistribution;Cancer Model;Cancer Therapy;Cell Division;Chemical Synthesis;Chemotherapy;Clinic;Clinical Trials;Collaborations;Combined Modality Therapy;Copolymer;Cytidine;Data;Design;Development;Dna;Dose;Dose-Limiting;Drug Carriers;Drug Combinations;Drug Delivery Systems;Evaluation;Fda Approved;Gemcitabine;Generations;Goals;In Vivo;Innovation;Investigational Drugs;Laboratories;Legal Patent;Malignant Neoplasm Of Ovary;Maximum Tolerated Dose;Methacrylamide;Microtubules;Molecular Weight;Mus;Novel;Nucleoside Analog;Oligopeptides;Organ;Ovarian Carcinoma;Ovarian Neoplasm;Paclitaxel;Permeability;Pharmaceutical Preparations;Phase;Polymers;Preclinical Study;Protein Aminoacid Sequence;Public Health Relevance;Publications;Regimen;Research;Resource Allocation;Scale Up;Side;Site;Small Business Technology Transfer Research;Staging;Success;System;Therapeutic;Time;Timeline;Tomography, Emission-Computed, Single-Photon;Toxic Effect;Translations;Treatment Efficacy;Treatment Outcome;Treatment Protocols;Tripolyphosphate;Tumor;United States National Institutes Of Health;Vertebral Column;X-Ray Computed Tomography;