Pharmacokinetic evaluation of liposomal nanoparticle-encapsulated nucleic acid drug: A combined study of dynamic PET imaging and LC/MS/MS analysis.
J Control Release
; 294: 185-194, 2019 01 28.
Article
em En
| MEDLINE
| ID: mdl-30529725
ABSTRACT
In vivo biodistribution analyses, especially in tumors, of nucleic acids delivered with nanoparticles are important to develop drug delivery technologies for medical use. We previously developed wrapsome® (WS), an ~100â¯nm liposomal nanoparticle that can encapsulate siRNA, and reported that WS accumulates in tumors in vivo and inhibits their growth by an enhanced permeability and retention effect. In the present study, we evaluated the pharmacokinetics of nucleic acid-containing nanoparticles by combining dynamic positron emission tomography (PET) imaging and liquid chromatography-tandem mass spectrometry (LC/MS/MS) analysis. An 18-mer phosphorothioate oligodeoxynucleotide (ODN), trabedersen, was used as a model drug and was encapsulated in WS. Dynamic PET imaging and time-activity curve analysis of WS-encapsulated 64Cu-labeled ODNs administered to mice with MIA PaCa-2 subcutaneous xenograft tumors showed tumor accumulation (~3% injected dose per gram (%ID/g)) and liver accumulation (~30 %ID/g) at 24â¯h. Under these conditions, LC/MS/MS analysis showed that the level of intact ODNs was 1.62 %ID/g in the tumor and 1.70 %ID/g in the liver. From these pharmacokinetic data, the intact/accumulated ODN ratios were calculated using the following equation intact/accumulated ODN ratio (%)â¯=â¯%ID/g LC/MS/MS, tissue, mean/%ID/g PET, tissue, meanâ¯×â¯100. Interestingly, the ratios for the tumor and kidney were maintained at 20-50% over 48â¯h after administration of the WS-encapsulated form. In contrast, the ratio for the liver rapidly decreased at 24â¯h, showing the same pattern as that for naked ODN. These different patterns indicate that WS effectively protected the ODN in the tumor and kidney, but protected it less efficiently in the liver. A combined approach of dynamic PET imaging and LC/MS/MS analysis will assist the development of nanoparticle-encapsulated nucleic acid drugs, such as those using WSs, to determine their detailed pharmacokinetics.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Oligonucleotídeos
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Nanopartículas
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Neoplasias
Limite:
Animals
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Female
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Humans
Idioma:
En
Revista:
J Control Release
Assunto da revista:
FARMACOLOGIA
Ano de publicação:
2019
Tipo de documento:
Article