Evaluation of anticancer effect of micelle-encapsulated doxorubicin using gamma-distributed delay model

Yamashita, Shugo; Kume, Aomi; Tsujimoto, Nao; Nozaki, Saya; Kimura, Shunsuke; Kiriyama, Akiko

doi:10.1016/j.jddst.2023.105244

Cited by 1 publication

(15 citation statements)

References 26 publications

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“…In contrast, PPDF-Hyd-DOX exhibited a higher intratumoral maximum DOX concentration (Tumor C max ) and tumoral mean residence time (tumor mean to retention time [MRT]). Compared to our previous reported DOX alone results, the PK parameters of these micelle formations were 6.2-fold higher in tumor C max , and 3.4-fold higher in tumor MRT . The fitting curves calculated from the PK compartmental analyses are shown in Figure .…”

Section: Resultsmentioning

confidence: 99%

“…We emphasized the significance of the time-delay function in characterizing drug release from polymeric micelles when constructing a PK model for polymeric micelles. A PK model for sustained-release polymeric micelles was constructed using the GDD function . We applied a similar approach to PPDF-Hyd-DOX, but the pH-responsive release did not require a time delay function.…”

Section: Discussionmentioning

confidence: 99%

“…The sonicated solution was subsequently passed through a membrane filter (0.22 μm) to prepare active-targeting pH-sensitively released FA-PPDF-Hyd-DOX micelles. Images of AFM were obtained as previously described 12 (Figure S3). Next, particle analysis was performed using SPM manager software (Ver.…”

Section: Peg-poly[d(-hyd-dox)/f] N Synthesismentioning

confidence: 99%

“…In our previous study, we implanted microdialysis probes into tumors to collect interstitial fluid . This method enabled the frequent sampling of intratumoral doxorubicin from rats intravenously administered with DOX.…”

Section: Introductionmentioning

confidence: 99%

“…Additionally, a pharmacodynamic (PD) model is required to assess the contribution of the DDS function to pharmacological effects. In previous studies, we integrated pharmacokinetic–pharmacodynamic (PK–PD) analysis with conventional PD and PK models to elucidate sustained release . Although the DOX potency typically remains constant regardless of the formulation, the conventional PD model assessment revealed markedly varied drug potency between DOX and DOX–micelle.…”

Section: Introductionmentioning

confidence: 99%

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Pharmacokinetic–Pharmacodynamic Analysis of pH-Responsive Doxorubicin-Releasing Micelles with Anticancer Activity

Yamashita,

Imanishi,

Ueki

et al. 2024

Mol. Pharmaceutics

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This study aimed to investigate the effect of in vivo pH-responsive doxorubicin (DOX) release and the targetability of pilot molecules in folic acid (FA)-modified micelles using a pharmacokinetic−pharmacodynamic (PK−PD) model. The time profiles of intratumoral DOX concentrations in Walker256 tumor-bearing rats were monitored using a microdialysis probe, followed by compartmental analysis, to evaluate intratumoral tissue pharmacokinetics. Maximal DOX was released from micelles 350 min after the administration of pH-responsive DOX-releasing micelles. However, FA modification of the micelles shortened the time to peak drug concentration to 150 min. Additionally, FA modification resulted in a 27-fold increase in the tumor inflow rate constant. Walker256 tumor-bearing rats were subsequently treated with DOX, pH-responsive DOX-releasing micelles, and pH-responsive DOX-releasing FA-modified micelles to monitor the tumor growth−time profiles. An intratumoral threshold concentration of DOX (55−64 ng/g tumor) was introduced into the drug efficacy compartment to construct a PD model, followed by PK−PD analysis of the tumor growth−time profiles. Similar results of threshold concentration and drug potency of DOX were obtained across all three formulations. Cell proliferation was delayed as the drug delivery ability of DOX was improved. The PK model, which was developed using the microdialysis method, revealed the intratumoral pH-responsive DOX distribution profiles. This facilitated the estimation of intratumoral PK parameters. The PD model with threshold concentrations contributed to the estimation of PD parameters in the three formulations, with consistent mechanisms observed. We believe that our PK−PD model can objectively assess the contributions of pH-responsive release ability and pilot molecule targetability to pharmacological effects.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Peg-poly[d(-hyd-dox)/f] N Synthesismentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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