Tumor-preferential sustained drug release enhances antitumor activity of block copolymer micelles.
Nanoparticles are widely used as drug carriers for controlled, tumor-targeted delivery of various anticancer agents that have biopharmaceutical limitations such as water solubility and tissue permeability. Growing evidence suggests that nanoparticles not only reduce toxic side effects of anticancer drugs but also improve the therapeutic efficacy as a function of their drug-release profile. The purpose of this study is to confirm such hypothetical effects of tunable drug release on improving antitumor activity of nanoparticles in vitro and in vivo, using block copolymer micelles as drug carriers. Micelles were prepared from poly(ethylene glycol)-poly(aspartate) block copolymers modified with hydrazide (HYD), aminobenzoate hydrazide (ABZ) and glycine hydrazide (GLY) linkers to achieve a pH-dependent, tunable release of doxorubicin (DOX), a model anticancer drug. Regardless of the drug-release profile, all three micelles showed similar properties in vitro, such as pH-dependent drug release, intracellular drug delivery and cancer cell growth inhibition. However, micelles releasing DOX slowly in vitro showed that the most effective antitumor activity in vivo, compared to the micelles releasing drugs faster. These results demonstrate that tumor-preferential sustained drug release can enhance the antitumor activity of the micelles.
Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky , Lexington, KY , USA.
Andrei
A
Ponta
Younsoo
Y
Bae
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004317:Doxorubicin / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D004337:Drug Carriers / Q000138:chemical synthesis / Q000737:chemistry*; D004339:Drug Compounding; D065546:Drug Liberation; D005260:Female; D006801:Humans; D016513:Mice, SCID; D008823:Micelles; D015394:Molecular Structure; D011092:Polyethylene Glycols / Q000138:chemical synthesis / Q000737:chemistry*; D023041:Xenograft Model Antitumor Assays
D000903:Antibiotics, Antineoplastic; D004337:Drug Carriers; D008823:Micelles; C493635:polyethylene glycol-block-polyaspartic acid; D011092:Polyethylene Glycols; D004317:Doxorubicin
Acid-labile linkers; doxorubicin; drug delivery; hydrazone; nanoparticles; pH-controlled drug release