Pharmaceutical differences between block copolymer self-assembled and cross-linked nanoassemblies as carriers for tunable drug release.
OBJECTIVE
To identify the effects of cross-linkers and drug-binding linkers on physicochemical and biological properties of polymer nanoassembly drug carriers.


METHODS
Four types of polymer nanoassemblies were synthesized from poly(ethylene glycol)-poly(aspartate) [PEG-p(Asp)] block copolymers: self-assembled nanoassemblies (SNAs) and cross-linked nanoassemblies (CNAs) to each of which an anticancer drug doxorubicin (DOX) was loaded by either physical entrapment or chemical conjugation (through acid-sensitive hydrazone linkers).


RESULTS
Drug loading in nanoassemblies was 27 ~ 56% by weight. The particle size of SNA changed after drug and drug-binding linker entrapment (20 ~ 100 nm), whereas CNAs remained 30 ~ 40 nm. Drug release rates were fine-tunable by using amide cross-linkers and hydrazone drug-binding linkers in combination. In vitro cytotoxicity assays using a human lung cancer A549 cell line revealed that DOX-loaded nanoassemblies were equally potent as free DOX with a wide range of drug release half-life (t(1/2) = 3.24 ~ 18.48 h, at pH 5.0), but 5 times less effective when t(1/2) = 44.52 h.


CONCLUSIONS
Nanoassemblies that incorporate cross-linkers and drug-binding linkers in combination have pharmaceutical advantages such as uniform particle size, physicochemical stability, fine-tunable drug release rates, and maximum cytotoxicity of entrapped drug payloads.
Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, 789 South Limestone, Lexington, Kentucky 40536, USA.
Hyun Jin
HJ
Lee
Younsoo
Y
Bae
D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage* / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003432:Cross-Linking Reagents / Q000737:chemistry*; D004317:Doxorubicin / Q000008:administration & dosage* / Q000494:pharmacology; D004337:Drug Carriers / Q000737:chemistry*; D006801:Humans; D006835:Hydrazones / Q000737:chemistry; D008175:Lung Neoplasms / Q000188:drug therapy; D049329:Nanostructures / Q000737:chemistry*; D011092:Polyethylene Glycols / Q000737:chemistry*
D000903:Antibiotics, Antineoplastic; D003432:Cross-Linking Reagents; D004337:Drug Carriers; D006835:Hydrazones; C493635:polyethylene glycol-block-polyaspartic acid; D011092:Polyethylene Glycols; D004317:Doxorubicin