pH-responsive biodegradable micelles based on acid-labile polycarbonate hydrophobe: synthesis and triggered drug release.
pH-responsive biodegradable micelles were prepared from block copolymers comprising of a novel acid-labile polycarbonate hydrophobe and poly(ethylene glycol) (PEG). Two new cyclic aliphatic carbonate monomers, mono-2,4,6-trimethoxybenzylidene-pentaerythritol carbonate (TMBPEC, 2a) and mono-4-methoxybenzylidene-pentaerythritol carbonate (MBPEC, 2b) were designed and successfully synthesized via a two-step procedure. The ring-opening polymerization of 2a or 2b in the presence of methoxy PEG in dichloromethane at 50 °C using zinc bis[bis(trimethylsilyl)amide] as a catalyst yielded the corresponding block copolymers PEG-PTMBPEC (3a) or PEG-PMBPEC (3b) with low polydispersities (PDI 1.03-1.04). The copolymerization of D,L-lactide (DLLA) and 2a under otherwise the same conditions could also proceed smoothly to afford PEG-P(TMBPEC-co-DLLA) (3c) block copolymer. These block copolymers readily formed micelles in water with sizes of about 120 nm as determined by dynamic light scattering (DLS). The hydrolysis of the acetals of the polycarbonate was investigated using UV/vis spectroscopy. The results showed that the acetals of micelles 3a, while stable at pH 7.4 are prone to rapid hydrolysis at mildly acidic pH of 4.0 and 5.0, with a half-life of 1 and 6.5 h, respectively. The acetal hydrolysis resulted in significant swelling of micelles, as a result of change of hydrophobic polycarbonate to hydrophilic polycarbonate. In comparison, the acetals of PMBPEC of micelles 3b displayed obviously slower hydrolysis at the same pH. Both paclitaxel and doxorubicin could be efficiently encapsulated into micelles 3a achieving high drug loading content (13.0 and 11.7 wt %, respectively). The in vitro release studies showed clearly a pH dependent release behavior, that is, significantly faster drug release at mildly acidic pH of 4.0 and 5.0 compared to physiological pH. These pH-responsive biodegradable micelles are promising as smart nanovehicles for targeted delivery of anticancer drugs.
Chen
Wei
W
Biomedical Polymers Laboratory, College of Chemistry, Chemical Engineering and Materials Science, Soochow University, Suzhou 215123, People's Republic of China.
Meng
Fenghua
F
Li
Feng
F
Ji
Shun-Jun
SJ
Zhong
Zhiyuan
Z
D000970:Antineoplastic Agents / Q000008:administration & dosage; D004337:Drug Carriers / Q000737:chemistry*; D016503:Drug Delivery Systems / Q000379:methods; D006863:Hydrogen-Ion Concentration; D008823:Micelles; D053758:Nanoparticles / Q000737:chemistry / Q000627:therapeutic use; D011076:Polycarboxylate Cement / Q000138:chemical synthesis*; D011092:Polyethylene Glycols / Q000737:chemistry; D058105:Polymerization
D000970:Antineoplastic Agents; D004337:Drug Carriers; D008823:Micelles; D011076:Polycarboxylate Cement; C005506:polycarbonate; D011092:Polyethylene Glycols