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Brief Description

UCSF investigators have developed a novel targeted pro-drug technology that can selectively deliver a chemotherapeutic payload to cells in areas of high concentrations of endogenous free ferrous iron. The pro-drug can be conjugated to a variety of existing and novel pharmacologically active compounds to increase their therapeutic window and lower systemic toxicity by increasing the selectivity of their delivery. Applications include therapies for cancer and malaria and as imaging agents. 

Full Description

BACKGROUND:

Pro-drug technologies are commonly employed to improve the membrane permeability or solubility of drugs. In contrast, targeted pro-drugs are intended to deliver a therapeutic payload to specific cells or proteins, but such technologies have typically relied on antibodies for selective delivery. Few targeted small molecule pro-drugs have been described to date; those that have seek to exploit a proteolytic event or a change in local pH to effect delivery of the therapeutic payload.  

DESCRIPTION:

UCSF investigators have developed a novel targeted pro-drug strategy that exploits unique biological and chemical characteristics of local cellular environments to selectively deliver a chemotherapeutic payload. Specifically, the pro-drug technology selectively releases a therapeutic agent in the presence of endogenous unbound ferrous iron and/or unbound heme.    

The therapeutic agent can be conjugated to the pro-drug moiety via a variety of chemical linkages including a carbamate, a carbonate, an amine, an ether, or a thioether.  The pro-drug linker is 'traceless' so that no additional chemical matter is retained by the drug after its release. Thus, the approach is applicable to existing agents, provided they possess suitable chemical functionality (an amine, alcohol, or thiol) for conjugation to the pro-drug species. Finally, the pro-drug design incorporates a variable position that can be modified to improve solubility, membrane permeability, or absorption, distribution, metabolism, and elimination (ADME) properties.  

As a proof of concept for the utility of the pro-drug technology, the UCSF investigators have successfully synthesized a number of pro-drugs and studied their behavior in malaria-infected erythrocytes, which are known to have a high endogenous free ferrous iron concentration [1]. A chemical-biological approach employing activity-based probes was used to study the release in cells of an irreversible cysteine protease inhibitor from its pro-drug form. From these studies it was determined that the drug was released with a half-life of approximately two hours in cells and that released drug exerted an antimalarial effect equal to that of its parent form. Hence, pro-drugs based on this technology are cell permeable, and release their payload in a therapeutically relevant timeframe in cells.  

Furthermore, in vivo studies of malaria-infected mice treated with the targeted pro-drug compound at an advanced stage of infection resulted in i) on-target effects equivalent to administration of the parent drug species, ii) greatly reduced off-target effects for the prodrug as compared to the parent drug administered alone, iii) improved efficacy and reduced toxicity as compared to direct administration of parent drug. Notably, administration of the pro-drug was well tolerated and produced cure while treatment with parent drug at equivalent dosage produced severe toxicity.    

Through the use of fluorescent probes incorporating the pro-drug moiety, the investigators have further demonstrated that the probes specifically accumulate in iron(II)-rich areas of a cell [2].  

A patent application has been filed on the pro-drugs used in the proof of concept studies and the investigators are currently developing next-generation iron(II)-targeted pro-drugs with improved in vivo stability and PK properties.   

Advantages

• Robust pro-drug chemistry
  
  
• Good stability in normal tissues, where concentrations of free iron(II) are exceedingly low


• Reduced total exposure of patient to active drug species 
  


• Targeted delivery of potentially toxic chemotherapy to sites of disease


• Compatibility with a broad range of therapeutics and a variety of chemical functionalities 
  
  
• Potentially orally available

Applications

• Imaging agents


• Drug delivery: Selective delivery of an approved or novel therapeutic agent for treatment of any condition where the targeting to higher than normal conditions of ferrous iron is of therapeutic benefit.
  

• Targeted delivery of MMP or HDAC inhibitors to minimize effects on off-target metalloproteases

Cancer: Iron is essential for cell growth and many cancers (e.g. prostate, colon, and breast) upregulate the expression of proteins involved in iron acquisition, notably the transferrin receptor (Tf-R). In a recent study involving breast cancer patients at Mass. General Hospital, it was found that patient's primary breast cancer cells typically expressed 5-100 fold higher levels of Tf-R than neighboring healthy breast tissue. The binding of iron(III)-loaded transferrin to Tf-R is followed by endocytosis and the release of soluble ferrous(II)iron, prior to its storage as ferritin. It is this intracellular free unbound ferrous iron that can, in principle, serve as the trigger for drug release with the UCSF pro-drug technology.  A number of approaches targeting Tf-R with antibody-drug conjugates are being explored but no other small molecule-based approach has yet been advanced. The relatively higher concentration of iron(II) in cancer cells can be exploited to trigger selective drug release in those cells/tissues using the UCSF pro-drug technology. Initial treatment with one of the approved therapeutic forms of inorganic iron followed by administration of the pro-drug is another potential therapeutic approach. 

Malaria: Hemoglobin-scavenging parasites possess compartments rich in redox-active ferrous iron (including unbound heme) that can serve as the chemical trigger for the UCSF pro-drug technology to deliver a drug selectively to pathogenic parasites. These studies in malaria parasites have clearly demonstrated that pro-drugs based on UCSF technology undergo iron(II) activation and drug release as designed.   

Patent Status

Country	Type	Number	Dated	Case
United States Of America	Published Application	20110190291	08/04/2011	2008-073

Publications

1. Mahajan, S.S. et al. A Fragmenting Hybrid Approach for Targeted Delivery of Multiple Therapeutic Agents to the Malaria Parasite. 2011. ChemMedChem. 6, 415-419.  
   


2. Hartwig, C.L et al. Investigating the Antimalarial Action of 1,2,4-Trioxolanes with Fluorescent Chemical Probes. 2011. J. Med. Chem. 54, 8207-8213.

Other Information

Contact

Dior R. Baumjohann / dior.baumjohann@ucsf.edu / tel: View Phone Number. Please reference Tech ID #19014.

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