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Approaches to tracking and targeting drug interactions in living systems
Author(s) -
Knudsen Giselle M.,
Rozhkov Roman V,
Fatig Raymond O,
Robinson J. Paul,
Schweitzer Dirk,
Helquist Paul,
Davisson V. Jo
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.5.a941-c
Subject(s) - natural product , geldanamycin , chemistry , computational biology , molecular binding , small molecule , nanoparticle , drug , anticancer drug , nanotechnology , heat shock protein , biophysics , combinatorial chemistry , molecule , biology , biochemistry , materials science , hsp90 , pharmacology , gene , organic chemistry
We are developing micro‐ and nano‐scale particle probes to elucidate the molecular level interactions of anticancer natural products in living systems. Geldanamycin is a well known anticancer natural product with tight binding affinity for heat shock protein 90, and these investigations have focused on the effects of the nanoparticle structural design on the cellular drug localization by cytometry. Our results indicate that nanoparticle uptake is dependent upon the density of geldanamycin molecules per particle, where the molecular load has been determined by sedimentation and fluorescence spectroscopic analyses. An alternative set of particle‐based technologies were employed to assess the mechanism of action of a novel class of marine macrolides called iejimalides. Drug‐bead‐based proteomic methods using an affinity purification strategy coupled with high‐throughput MS/MS analysis have identified multiple binding partners and protein complexes. These two different scales of particle‐based probes illustrate how different ranges of binding affinities and in‐cell behavior of distinct natural product drugs can be assessed. In particular, the capacity to impart drug like properties to appropriately sized particles opens new avenues for analyzing the complexity of natural product cellular pharmacology. This work was supported in part by the Purdue Cancer Center NIH training grant number 5T32CA09634‐14, and NIH R21CA91116 (VJD).