Most existing anti-cancer drug therapies are relatively ineffective due to the presence of two bottleneck limitations: [1] the lack of selectivity of drug action towards cancer cells as opposed to normal tissues;and [2] the impermeability of the cell membrane that restricts drug uptake to simply small and hydrophobic agents. Proposed herein is a novel drug delivery approach that not only carries the potential to subdue these two limitations simultaneously but also be applied universally to delivery of drugs of all types (e.g. large or small) for treatment of cancers of all types (e.g. breast tumor, malignant melanoma). The approach utilizes the proven and unmatched trans-membrane ability of the so-called protein transduction domain (PTD) peptides (e.g. TAT from HIV protein) to ferry attached species across the membrane barrier in achieving highly effective cellular drug uptake, as well as the targeting and prodrug features to, yield selective drug actions and abort drug-induced toxic side effects. Briefly, the approach consists of a large complex made of two components: [1] a targeting component consists of a specific targeting moiety (e.g. antibody) linked with a heparin molecule and [2] a drug component is made by coupling, via cleavable S-S bonds, the delivered drug to a PTD peptide. These two components can associate automatically by a charge-charge interaction between the highly anionic heparin and cationic PTD. It has been confirmed in the literature that binding PTD with heparin would mask its trans-membrane activity;presumably due to inhibition of PTD adsorption to the cell surface. This prodrug feature would avoid drug uptake by normal cells, alleviating drug-induced toxic effects. Following tumor targeting by the antibody on the drug complex, protamine sulfate, a clinical heparin antidote that is known to bind heparin stronger than any existing PTD peptide, will be administered to unmask heparin-inhibition and restore the trans-membrane activity of PTD on the PTD-Drug conjugate. A study of the targeting pharmacokinetics will be carried out prior to protamine injection to determine the optimal dosing time of protamine (defined as the time when a maximum degree of the drug complexes has accumulated at the tumor target but a minimum amount is remained in the circulation), so that systemic toxicity caused by non-specific uptake of the PTD-Drug conjugates by normal tissues can be avoided. Once inside the tumor, the drug will be released by degradation of the S-S linkage by elevated cytosolic levels of glutathione and reductase activity, inducing apoptosis to primary tumor cells. If a large protein drug is used for delivery, the released drug will be unaffected by the multidrug resistant (MDR) effect because proteins are impermeable to cell membrane. Preliminary studies yielded extremely promising results, as a nearly complete tumor regression was observed in mice by using this approach in delivering a cell-impermeable protein toxin. In this application, we plan to conduct a full-scale study aimed at demonstrating the real-time feasibility and utility of this delivery system. A small conventional anti-tumor agent (doxorubicin) and a large hydrophilic protein drug (gelonin) are selected to represent the full spectrum of possible anti-tumor agents, whereas a highly effective vascular targeting strategy based on the use of VEGF121 is chosen to test the system in treating mice harboring a model CT-26 solid tumor. Aside from the universal applicability of this system to cancer treatment, the system could lead to discovery and development of a new arena of drugs that show great therapeutic promise but considered unusable due to poor cell uptake or acute toxic effects. To this regard, the true value and impact of this project is significant, far-reaching, and prevalent.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA114612-05
Application #
7575750
Study Section
Special Emphasis Panel (ZRG1-SBIB-G (03))
Program Officer
Fu, Yali
Project Start
2005-05-04
Project End
2011-03-31
Budget Start
2009-04-01
Budget End
2011-03-31
Support Year
5
Fiscal Year
2009
Total Cost
$233,861
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Shin, Meong Cheol; Min, Kyoung Ah; Cheong, Heesun et al. (2016) Preparation and Characterization of Gelonin-Melittin Fusion Biotoxin for Synergistically Enhanced Anti-Tumor Activity. Pharm Res 33:2218-2228
Shin, Meong Cheol; Zhao, Jingwen; Zhang, Jian et al. (2015) Recombinant TAT-gelonin fusion toxin: synthesis and characterization of heparin/protamine-regulated cell transduction. J Biomed Mater Res A 103:409-419
Shin, Meong Cheol; Zhang, Jian; Min, Kyoung Ah et al. (2015) PTD-Modified ATTEMPTS for Enhanced Toxin-based Cancer Therapy: An In Vivo Proof-of-Concept Study. Pharm Res 32:2690-703
He, Huining; Ye, Junxiao; Wang, Yinsong et al. (2014) Cell-penetrating peptides meditated encapsulation of protein therapeutics into intact red blood cells and its application. J Control Release 176:123-132
Zhang, Jian; Shin, Meong Cheol; Yang, Victor C (2014) Magnetic targeting of novel heparinized iron oxide nanoparticles evaluated in a 9L-glioma mouse model. Pharm Res 31:579-92
Shin, Meong Cheol; Zhang, Jian; Ah Min, Kyoung et al. (2014) Combination of antibody targeting and PTD-mediated intracellular toxin delivery for colorectal cancer therapy. J Control Release 194:197-210
Shin, Meong Cheol; Zhang, Jian; Min, Kyoung Ah et al. (2014) Cell-penetrating peptides: achievements and challenges in application for cancer treatment. J Biomed Mater Res A 102:575-87
Zhang, Jian; Shin, Meong Cheol; David, Allan E et al. (2013) Long-circulating heparin-functionalized magnetic nanoparticles for potential application as a protein drug delivery platform. Mol Pharm 10:3892-902
Park, Yoon Shin; David, Allan E; Park, Kyung Min et al. (2013) Controlled release of simvastatin from in situ forming hydrogel triggers bone formation in MC3T3-E1 cells. AAPS J 15:367-76
Min, Kyoung Ah; Shin, Meong Cheol; Yu, Faquan et al. (2013) Pulsed magnetic field improves the transport of iron oxide nanoparticles through cell barriers. ACS Nano 7:2161-71

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