Polymeric micelles for the pH-dependent controlled, continuous low dose release of paclitaxel.
Poly(ethylene glycol)-block-poly(aspartate-hydrazide) (PEG-p(Asp-Hyd)) was modified using either levulinic acid (LEV) or 4-acetyl benzoic acid (4AB) attached via hydrazone bonds. Paclitaxel (PTX) conjugated to the linkers formed PEG-p(Asp-Hyd-LEV-PTX) and PEG-p(Asp-Hyd-4AB-PTX). PEG-p(Asp-Hyd-LEV-PTX) and PEG-p(Asp-Hyd-4AB-PTX) assemble into unimodal polymeric micelles with diameters of 42 nm and 137 nm, respectively. PEG-p(Asp-Hyd-LEV-PTX) and PEG-p(Asp-Hyd-4AB-PTX) at a 1:1 and 1:5 molar ratio assemble into unimodal mixed polymeric micelles with diameters of 85 and 113 nm, respectively. PEG-p(Asp-Hyd-LEV-PTX) micelles release LEV-PTX faster at pH 5.0 than at pH 7.4 over 24 h. At pH 7.4 mixed polymeric micelles at 1:5 ratio show no difference in LEV-PTX release from PEG-p(Asp-Hyd-LEV-PTX) micelles. Mixed polymeric micelles at 1:5 molar ratio gradually release LEV-PTX at pH 5.0, with no release of 4AB-PTX. PEG-p(Asp-Hyd-LEV-PTX) micelles and mixed polymeric micelles exert comparable cytotoxicity against SK-OV-3 and MCF-7 cancer cell lines. In summary, mixed polymeric micelles based on PEG-p(Asp-Hyd-LEV-PTX) and PEG-p(Asp-Hyd-4AB-PTX) offer prospects for pH-dependent release of PTX, offering a novel prodrug strategy for adjusting its pharmacokinetic and pharmacodynamic properties for cancer therapy. If successful this delivery system offers an alternative new mode of delivery for paclitaxel with a new scope for its efficacy along with a minimal synthetic framework needed to accomplish this.
Alani
Adam W G
AW
Pharmaceutical Sciences Division, School of Pharmacy, University of Wisconsin, 777 Highland Ave, Madison, WI 53705, USA.
Bae
Younsoo
Y
Rao
Deepa A
DA
Kwon
Glen S
GS
D001565:Benzoates / Q000138:chemical synthesis / Q000737:chemistry; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006801:Humans; D006863:Hydrogen-Ion Concentration / Q000187:drug effects; D007982:Levulinic Acids / Q000138:chemical synthesis / Q000737:chemistry; D008027:Light; D009682:Magnetic Resonance Spectroscopy; D008823:Micelles; D017239:Paclitaxel / Q000737:chemistry / Q000494:pharmacology*; D010316:Particle Size; D011092:Polyethylene Glycols / Q000138:chemical synthesis* / Q000737:chemistry; D011506:Proteins / Q000138:chemical synthesis* / Q000737:chemistry; D012542:Scattering, Radiation
D001565:Benzoates; D007982:Levulinic Acids; D008823:Micelles; D011506:Proteins; C523990:poly(ethylene glycol)-poly(aspartate hydrazide); D011092:Polyethylene Glycols; C115900:4-acetylbenzoic acid; D017239:Paclitaxel; C032246:levulinic acid