Quantitative evaluation of the improvement in the pharmacokinetics of a nucleic acid drug delivery system by dynamic PET imaging with 18F-incorporated oligodeoxynucleotides

Mukai, Hidefumi; Ozaki, Daiki; Cui, Yilong; Kuboyama, Takeshi; Yamato-Nagata, Hiroko; Onoe, Kayo; Takahashi, Maiko; Wada, Yasuhiro; Imanishi, Takeshi; Kodama, Tetsuya; Obika, Satoshi; Suzuki, Masaaki; Doi, Hisashi; Watanabe, Yasuyoshi

doi:10.1016/j.jconrel.2014.02.014

Cited by 22 publications

(10 citation statements)

References 34 publications

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“…The ratios of Vd L /F of Chol‐ASO and Toc‐ASO to that of unchanged ASO were reasonable (5.5 and 6.2, as shown in Table 1) because the amounts of ASO after administration of Chol‐ASO and Toc‐ASO were approximately 3.5‐ to 6.3‐fold and 4.4‐ to 7.5‐fold higher than that of unconjugated ASO (Watanabe et al., 2016). Several studies also reported that Chol‐ASO showed much higher and more rapid accumulation in the liver compared with unconjugated ASO (Bijsterbosch et al., 2000; Mukai et al., 2014; Nishina et al., 2015). However, although we thought that a fraction of the dose was excreted to urine, the distribution ratio of ASO from plasma to kidney was not clear in the study.…”

Section: Resultsmentioning

confidence: 97%

Pharmacokinetic–pharmacodynamic modeling for hepatic delivery and efficacy of antisense oligonucleotides with lipophilic ligands in mice

Watanabe

Katsube

2021

Biopharm & Drug Disp

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Conjugation with lipophilic ligands such as cholesterol and α‐tocopherol dramatically improves the delivery and efficacy of antisense oligonucleotides (ASOs) in the liver. To estimate the hepatic ASO concentration and the efficacy of ASOs conjugated with lipophilic ligands in mice, we constructed a pharmacokinetic‐pharmacodynamic (PK‐PD) model that consisted of a two‐linear compartment model for the plasma and the hepatic ASO concentration, and two indirect response models for the hepatic apolipoprotein B (Apo‐B) mRNA and plasma total cholesterol. The model provided a good fit of the hepatic ASO concentration although it showed an overprediction of Apo‐B mRNA and an underprediction of the plasma total cholesterol within 2‐fold at a later time after single intravenous administration of ASOs conjugated with lipophilic ligands. In addition, the model simulations indicated that the efficacy at a dose regimen of ASOs conjugated with lipophilic ligands (0.2 mg/kg, once a week) in mice was comparable to that at an effective dose of unchanged ASO (2.5 mg/kg, once a week). Although further studies are required to refine the parameters of the PK–PD model, this approach could be used to guide dose‐ranging pharmacological studies for ASOs conjugated with lipophilic ligands in mice.

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Section: Resultsmentioning

confidence: 97%

Pharmacokinetic–pharmacodynamic modeling for hepatic delivery and efficacy of antisense oligonucleotides with lipophilic ligands in mice

Watanabe

Katsube

2021

Biopharm & Drug Disp

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“…115) They confirmed that drug was more efficiently transferred to the olfactory bulb and brainstem by N2B delivery of Tat peptide-modified nanomicelles than the free drug. 120) They also prepared Tat-modified micelles loaded with camptothecin (CPT) and siRNA for the treatment of glioma and found that the micellar formulation suppressed tumor growth and increased survival times. 115) Because of the large gene vector size, it was assumed that gene transfection through N2B delivery would be difficult.…”

Section: Nose-to-brain Drug Deliverymentioning

confidence: 99%

Recent Strategies for Targeted Brain Drug Delivery

2020

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Because the brain is the most important human organ, many brain disorders can cause severe symptoms. For example, glioma, one type of brain tumor, is progressive and lethal, while neurodegenerative diseases cause severe disability. Nevertheless, medical treatment for brain diseases remains unsatisfactory, and therefore innovative therapies are desired. However, the development of therapies to treat some cerebral diseases is difficult because the blood-brain barrier (BBB) or blood-brain tumor barrier prevents drugs from entering the brain. Hence, drug delivery system (DDS) strategies are required to deliver therapeutic agents to the brain. Recently, brain-targeted DDS have been developed, which increases the quality of therapy for cerebral disorders. This review gives an overview of recent brain-targeting DDS strategies. First, it describes strategies to cross the BBB. This includes BBB-crossing ligand modification or temporal BBB permeabilization. Strategies to avoid the BBB using local administration are also summarized. Intrabrain drug distribution is a crucial factor that directly determines the therapeutic effect, and thus it is important to evaluate drug distribution using optimal methods. We introduce some methods for evaluating drug distribution in the brain. Finally, applications of brain-targeted DDS for the treatment of brain tumors, Alzheimer's disease, Parkinson's disease, and stroke are explained.

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“…Mukai et al reported that a cholesterolconjugated ASO accumulated in the liver approximately at three times a higher amount than that of unconjugated (29). Wada et al designed a Triethylenglycol (TEG)-disulfate linker as a cleavable spacer between cholesterol and ASO.…”

Section: Cholesterol-conjugated Asomentioning

confidence: 99%