Drug discovery is a costly and inefficient process. Many promising hits identified from initial screening are often excluded from further investigation due to their poor water solubility and/or low bioavailability. Incorporating drug formulation expertise early in the drug discovery process represents an important strategy to facilitate preclinical and clinical evaluations of promising candidates that are poorly water soluble. JP4-039 and XJB5- 131 are stable nitroxide (4-amino-TEMPO) antioxidants conjugated to a peptide fragment derived from gramicidin S to facilitate their enrichment in mitochondria. Therapeutic effects of these novel compounds have been extensively demonstrated in rat hemorrhagic shock model and various radiation models in mice. One of the major hurdles for these compounds to advance into clinical applications is their poor water solubility. Organic solvents such as ethanol, DMSO, Cremophor EL/ethanol had to be used in the past for the assessment of their in vivo activity. We initially developed an emulsion-based formulation that could be used for either systemic (i.p. and i.v.) or topical (skin) application. However JP4-039-loaded emulsion formulation is relatively unstable. The drug is slowly disassociated from the particles over time. Low drug loading capacity and formulation instability are common problems in formulating agents that are moderately hydrophobic, mostly due to inadequate mixing of the insufficiently hydrophobic agents with the highly lipophilic aliphatic chains in surfactants and oil core of emulsions. Drugs that are initially mixed with oil core tend to slowly move to the interface of emulsion particles and eventually are disassociated from the particles. We hypothesize that drugs that are poorly water soluble and moderately hydrophobic can be effectively incorporated into emulsion or micellar formulations via the use of a novel surfactant that has a built-in drug-interactive domain between the hydrophilic PEG and the lipophilic anchor. JP4-039 will be used as a model drug to test the hypothesis.
Three aims will be pursued in this project.
In Aim 1, we will synthesize and characterize a number of PEG-lipopeptides with various interactive domains to identify the optimal structure for micellar formulation of JP4-039.
In Aim 2, we will examine the in vivo pharmacokinetics and biodistribution of JP4-039- loaded micelles.
In Aim 3, we will investigate the therapeutic efficacy of JP4-039-loaded micelles in mouse models of irradiation and hemorrhagic shock. Successful completion of this study will lead to the development of a new strategy that will facilitate the in vivo application of not only JP4-039 but also many other therapeutics that are poorly water soluble and difficult to formulate with existing lipidic systems

Public Health Relevance

Successful completion of this study will lead to the development of a new strategy that will facilitate the in vivo application of not only JP4-039 (a promising mitochondria-targeted antioxidant) but also many other therapeutics that are poorly water soluble and difficult to formulate with existing lipidic systems.

National Institute of Health (NIH)
Research Project (R01)
Project #
Application #
Study Section
Gene and Drug Delivery Systems Study Section (GDD)
Program Officer
Okita, Richard T
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Pittsburgh
Schools of Pharmacy
United States
Zip Code
Lu, Jianqin; Zhao, Wenchen; Huang, Yixian et al. (2014) Targeted delivery of Doxorubicin by folic acid-decorated dual functional nanocarrier. Mol Pharm 11:4164-78
Chen, Yichao; Zhang, Xiaolan; Lu, Jianqin et al. (2014) Targeted delivery of curcumin to tumors via PEG-derivatized FTS-based micellar system. AAPS J 16:600-8
Zhang, Xiaolan; Huang, Yixian; Zhao, Wenchen et al. (2014) Targeted delivery of anticancer agents via a dual function nanocarrier with an interfacial drug-interactive motif. Biomacromolecules 15:4326-35
Zhang, Peng; Lu, Jianqin; Huang, Yixian et al. (2014) Design and evaluation of a PEGylated lipopeptide equipped with drug-interactive motifs as an improved drug carrier. AAPS J 16:114-24
Zhang, Xiaolan; Huang, Yixian; Li, Song (2014) Nanomicellar carriers for targeted delivery of anticancer agents. Ther Deliv 5:53-68
Zhang, Yifei; Huang, Yixian; Zhao, Wenchen et al. (2014) Fmoc-conjugated PEG-vitamin E2 micelles for tumor-targeted delivery of paclitaxel: enhanced drug-carrier interaction and loading capacity. AAPS J 16:1282-91
Lu, Jianqin; Zhao, Wenchen; Liu, Hao et al. (2014) An improved D-?-tocopherol-based nanocarrier for targeted delivery of doxorubicin with reversal of multidrug resistance. J Control Release 196:272-86
Zhang, Peng; Huang, Yixian; Liu, Hao et al. (2014) A PEG-Fmoc conjugate as a nanocarrier for paclitaxel. Biomaterials 35:7146-56
Zhang, Xiaolan; Liu, Ke; Huang, Yixian et al. (2014) Reduction-sensitive dual functional nanomicelles for improved delivery of paclitaxel. Bioconjug Chem 25:1689-96
Zhang, Xiaolan; Huang, Yixian; Zhao, Wenchen et al. (2014) PEG-farnesyl thiosalicylic acid telodendrimer micelles as an improved formulation for targeted delivery of paclitaxel. Mol Pharm 11:2807-14

Showing the most recent 10 out of 11 publications