Small-Molecule Therapeutics

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Our Small-Molecule Therapeutics Program focuses on small-molecule compounds and drugs and their therapeutic effects on diseases and disorders related to iron transport and metabolism. Many human diseases result from hereditary or acquired deficiencies of iron-transporting protein function that diminishes transmembrane iron flux in distinct sites and directions. Because other iron-transport proteins remain active, labile iron gradients build up across the corresponding protein-deficient membranes. Earlier we explored the therapeutic effect of hinokitiol, a small-molecule natural product, on harnessing such gradients to restore iron transport into, within, and/or out of cells. We demonstrated that hinokitiol promotes gut iron absorption in rats lacking in DMT1 (iron-import protein) and mice that have decreased activity of ferroportin (iron-export protein), as well as hemoglobinization in zebrafish lacking in DMT1 and mitoferrin (mitochondrial iron importer). Our findings illuminate a general mechanistic framework for small molecule-mediated site- and direction-selective restoration of iron transport. Our study also suggests that small molecules that partially mimic the function of missing protein transporters of iron, and possibly other ions, may have potential in treating human diseases. Also, we have been investigating the therapeutic efficacy of several other small molecules on iron disorders. These include iron-binding compounds (e.g., chelators), ferroptosis inhibitors (e.g., ferrostatin-1), iron-transport regulators (e.g., ferristatin II), and antioxidants (e.g., thiol donors). For example, we found that ferristatin II treatment increases expression of hepcidin, a key regulator of iron transport and metabolism. The same molecule promotes the degradation of the transferrin receptor, an iron-import protein, leading to reduced iron uptake. These studies suggest that ferristatin II may have potential as a therapeutic agent for iron disorders. In addition, we recently explored the impact of a lipophilic metal chelator on genetic brain iron accumulation in mice and found that the chelator reverses brain iron accumulation and attenuates iron-induced oxidative stress, suggesting that the drug could have therapeutic potential for iron-related neurodegenerative diseases. Overall, our research provides a promising clinical advancement for various iron and metal disorders along with broad scientific and therapeutic implications.

 

References:

 

Grillo AS, SantaMaria AM, Kafina MD, Huston NC, Cioffi AG, Huston NC, Han M, Seo YA, Yien YY, Nardone C, Menon AV, Fan J, Svoboda DC, Anderson JB, Hong JD, Nicolau BG, Subedi K, Gewirth AA, Wessling-Resnick M, Kim J, Paw BH, Burke MD. Restored iron transport by a small molecule promotes absorption and hemoglobinization in animals. Science 2017; 356:608-616. PMID: 28495746.

 

Cheng R, Gadde R, Fan Y, Kulkarni N, Shevale N, Bao K, Choi HS, Betharia S, Kim J. Reversal of genetic brain iron accumulation by N,N’-bis(2-mercaptoethyl)isophthalamide, a lipophilic metal chelator, in mice. Arch Toxicol 2022; 96(7):1951-1962. PMID: 35445828.

 

Alkhateeb A, Buckett PD, Gardeck A, Kim J, Byrne SL, Fraenkel P, Wessling-Resnick M. The small molecule ferristatin II induces hepatic hepcidin expression in vivo and in vitro. Am J Physiol GI 2015; 308(12):G1019-26. PMID: 25907691.

 

Byrne SL, Buckett PD, Kim J, Luo F, Sanford J, Chen J, Enns C, Wessling-Resnick M. Ferristatin II promotes degradation of transferrin receptor-1 in vitro and in vivo. PLoS One 2013; 8:e70199. PMID: 23894616.

 

Ekaputri S, Choi EK, Sabelli M, Aring L, Green KJ, Chang J, Bao K, Choi HS, Iwase S, Kim J, Corradini E, Pietrangelo A, Burke MD, Seo YA. A small molecule redistributes iron in ferroportin-deficient mice and patient-derived primary macrophages. Proc Natl Acad Sci U S A 2022; 119(26):e2121400119. PMID: 35737834.
 

Nanomedicine and Drug Delivery

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Our Nanomedicine Therapeutics Program focuses on the development of controlled and targeted drug delivery platforms and nanomedicine to enhance the therapeutic efficacy as well as safety for the treatment of cardiovascular, neurological, and hematological complications associated with iron disorders. In particular, we are studying pharmacokinetics, pharmacodynamics, and toxicology of theranostic nanoparticles. These studies are aimed to evaluate the efficacy and tolerability of theranostic nanomedicine by using various in vitro and in vivo systems. For example, we have developed renal clearable nanochelators for iron overload therapy. Such ultrasmall deferoxamine-conjugated nanoparticles (nanochelators) circulate and collect excess iron in the bloodstream without distribution into other tissues, followed by exclusive urinary excretion due to their unique size and surface properties optimized for glomerular filtration. This approach avoids off-target toxicities of current FDA-approved, conventional small-molecule iron chelators and thereby significantly improves the safety in iron chelation therapy. In addition, we characterize the pharmacokinetics and pharmacodynamics of nanochelators in mice and rats to evaluate the bioavailability and administration route-dependent efficacy/toxicity of the nanochelators. Our work demonstrates that nanochelators reside in the body for a reasonable amount of time to collect excess iron and that iron-bound nanochelators are rapidly cleared via urine to facilitate iron excretion with no accumulation in the body after repeated doses. These pharmacokinetic and pharmacodynamic assessments allow us to design various drug delivery systems using nanoparticles and explore different routes of administration to optimize therapeutic efficacy and decrease potential tolerability and toxicity. Furthermore, we develop injectable thermosensitive hydrogels for a sustained release of nanochelators. Our study demonstrates that such hydrogels effectively reduce iron accumulation in the liver and spleen of mice, indicating their potential use in treating iron overload disorders. Overall, the development of renal-targeted nanochelators and the use of injectable hydrogels for sustained release of nanochelators are among the recent advancements in the field, and our research confirms the idea that nanochelators could be a promising alternative for the treatment of iron overload disorders.

 

References:

 

Park SH, Kim RS, Stiles WR, Jo M, Zeng L, Rho S, Baek Y, Kim J, Kim MS, Kang H, Choi HS. Injectable thermosensitive hydrogels for a sustained release of iron nanochelators. Adv Sci 2022; e2200872. PMID: 35343104.

 

Jones G, Zeng L, Stiles WR, Park SH, Kang H, Choi HS, Kim J. Pharmacokinetics and tissue distribution of deferoxamine-based nanochelator in rats. NanoMedicine 2022; 17(22):1649-1662. PMID: 36547231.

 

Debreli Coskun M, Kim J. Chapter 1: Route of Administration, Distribution, and Tissue Specific Challenges. In Organelle and Molecular Targeting. 2021; Ed. Milane L, Amiji MM. CRC Press.

 

Jones G, Goswami SK, Kang H, Choi HS, Kim J. Combating iron overload: A case for deferoxamine-based nanochelators. Nanomedicine 2020; 15:1341-1356. PMID: 32429801.

 

Kang H, Han M, Xue J, Baek Y, Chang J, Hu S, Nam HY, Jo M, El Fakhri G, Hutchens MP, Choi HS, Kim J. Renal clearable nanochelators for iron overload therapy. Nat Commun 2019; 10(1):5134. PMID: 31723130.

 

Kang H, Mintri S, Menon AV, Lee HY, Choi HS, Kim J. Pharmacokinetics, Pharmacodynamics and Toxicology of Theranostic Nanoparticles. Nanoscale 2015; 7:18848-18862. PMID: 26528835.