Combined strategies of apomorphine diester prodrugs and nanostructured lipid carriers for efficient brain targeting.
Our aim is to develop nanostructured lipid carriers (NLCs) for loading the apomorphine diester prodrugs, diacetyl apomorphine (DAA) and diisobutyryl apomorphine (DIA), into the brain. NLCs were prepared using sesame oil/cetyl palmitate as the lipid matrices. Experiments were performed with the objective of evaluating the physicochemical characteristics, drug release, safety and brain-targeting efficacy of the NLCs. The size of regular NLCs (N-NLCs) was 214 nm. The addition of Forestall (FE) and polyethylene glycol (PEG) to the NLCs (P-NLCs) increased the particle diameter to 250 nm. The zeta potentials of N-NLCs and P-NLCs were respectively shown to be - 21 and 48 mV. Diester prodrugs were more lipophilic and more chemically stable than the parent apomorphine. The hydrolysis study indicated that the prodrugs underwent bioconversion in plasma and brain extract, with DAA exhibiting faster degradation than DIA. Sustained release was achieved through the synergistic effect of integrating strategies of prodrugs and NLCs, with the longer carbon chain showing the slower release (DIA < DAA). None of the NLCs tested here exhibited a toxicity problem according to the examination of neutrophil lactate dehydrogenase (LDH) release and hemolysis. Results of a bioimaging study in mice showed that P-NLCs largely accumulated in the brain. The distribution duration of the fluorescent dye in the brain region was also prolonged by the nanocarriers.
Graduate Institute of Pharmaceutical Science, Chia Nan University of Pharmacy and Science, Tainan, Taiwan.
Kuo-Sheng
KS
Liu
Chih-Jen
CJ
Wen
Tzu-Chen
TC
Yen
K C
KC
Sung
Ming-Chuan
MC
Ku
Jhi-Joung
JJ
Wang
Jia-You
JY
Fang
D000818:Animals; D001058:Apomorphine / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics*; D001921:Brain / Q000378:metabolism*; D018491:Dopamine Agonists / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics; D008081:Liposomes / Q000737:chemistry*; D008657:Metabolic Clearance Rate; D051379:Mice; D008819:Mice, Nude; D053769:Nanocapsules / Q000008:administration & dosage / Q000737:chemistry*; D010168:Palmitates / Q000737:chemistry*; D012715:Sesame Oil / Q000737:chemistry*; D014018:Tissue Distribution
D018491:Dopamine Agonists; D008081:Liposomes; D053769:Nanocapsules; D010168:Palmitates; C006957:cetyl palmitate; D012715:Sesame Oil; D001058:Apomorphine