title: Nanoparticulate formulations of mithramycin analogs for enhanced cytotoxicity.
abstract: Mithramycin (MTM), a natural product of soil bacteria from the Streptomyces genus, displays potent anticancer activity but has been limited clinically by severe side effects and toxicities. Engineering of the MTM biosynthetic pathway has produced the 3-side-chain-modified analogs MTM SK (SK) and MTM SDK (SDK), which have exhibited increased anticancer activity and improved therapeutic index. However, these analogs still suffer from low bioavailability, short plasma retention time, and low tumor accumulation. In an effort to aid with these shortcomings, two nanoparticulate formulations, poly(ethylene glycol)-poly(aspartate hydrazide) self-assembled and cross-linked micelles, were investigated with regard to the ability to load and pH dependently release the drugs. Micelles were successfully formed with both nanoparticulate formulations of each drug analog, with an average size of 8.36 ± 3.21 and 12.19 ± 2.77 nm for the SK and SDK micelles and 29.56 ± 4.67 nm and 30.48 ± 7.00 nm for the SK and SDK cross-linked micelles respectively. All of the drug-loaded formulations showed a pH-dependent release of the drugs, which was accelerated as pH decreased from 7.4 to 5.0. The micelles retained biological activity of SK and SDK entrapped in the micelles, suppressing human A549 lung cancer cells effectively.
authors: Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY 40536-0596, USA.
authors: Daniel
authors: D
authors: Scott
authors: Jürgen
authors: J
authors: Rohr
authors: Younsoo
authors: Y
authors: Bae
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003692:Delayed-Action Preparations / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D004337:Drug Carriers / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008823:Micelles; D053758:Nanoparticles / Q000737:chemistry*; D010316:Particle Size; D008926:Plicamycin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D011092:Polyethylene Glycols / Q000737:chemistry; D011506:Proteins / Q000737:chemistry
chemical_list: D000903:Antibiotics, Antineoplastic; D003692:Delayed-Action Preparations; D004337:Drug Carriers; D008823:Micelles; D011506:Proteins; C523990:poly(ethylene glycol)-poly(aspartate hydrazide); D011092:Polyethylene Glycols; D008926:Plicamycin