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Communication Dans Un Congrès Année : 2022

Pharmacokinetic analysis and modelling to optimize radiolabeled-dendrimers biodistribution

Résumé

Aim/Introduction: Nanosizing promotes the penetration of substances into solid tumors via the enhanced permeability and retention effect. Hence, CERIMED and CINaM teams designed a supramolecular [68Ga]Ga-radiolabeled self-assembling dendrimer (A) for tumor imaging. Dendrimer A was first optimized through chemical modifications to lower exposure of healthy organs, leading to 4 new dendrimer formulations (B,C,D,E). The best dendrimer was then selected and functionalized with RGD at different ratios, generating 2 other dendrimers (F,G). To understand the impact of structural modifications on the dendrimers biodistribution, a pharmacokinetic (PK) study was performed. Materials and Methods: Two-hour-long microPET/CT and gamma-counting biodistribution data of each radiolabeled dendrimer were collected from Swiss mice (n=6). Non-compartmental analysis (NCA) and population compartmental analysis (PopCA) were achieved respectively with PKanalix and Monolix softwares. NCA was used to describe exposure and main PK parameters in blood and organs for each formulation. PopCA was based on a semi-mechanistic model constituted of 10 compartments and allowed to evaluate the impact of dendrimer type on transfer rate constants between compartments. Results: Functionalization with RGD did not impact pharmacokinetics, and dendrimers F and G behaved similarly to dendrimer E. Dendrimer E displayed the lowest systemic exposure (area under concentration versus time curve (AUC) of 38 %ID/mL.h versus 71-138 %ID/mL.h), and consistently the highest clearance CL (2.66 mL/h versus 0.83-1.48 mL/h) which could be attributed to a more efficient renal elimination as suggested by bladder data. The volume of distribution (Vd) was also higher than for other dendrimers (8.00 mL versus 3.95-5.65 mL), suggesting a wider distribution in the organism, in line with the higher concentrations observed at the earliest time points in the main organs. AUCs in the main organs were contrarily lower for dendrimer E, due to a shorter terminal half-life (HL) in organs. Dendrimer E also displayed a short blood HL (2.21 h versus 1.99-4.36 h). The semi-mechanistic model confirmed that dendrimer E was less long retained in the liver compared to the other dendrimers, with higher liver elimination constants. Renal elimination constant was also higher for dendrimer E, confirming a better renal excretion. Conclusion: PK studies allowed the selection of an optimal dendrimer displaying the lowest exposure of healthy organs and the fastest clearance for future functionalization studies. PopCA provided a mechanistic understanding of the differences in PK behavior, which might be partly ascribed to a switch between renal and hepatic elimination. The semi-mechanistic model is also a first step toward the development of a physiologically-based pharmacokinetic model, which could be a useful tool to predict PK behavior of dendrimers depending on their chemical structure.
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Dates et versions

hal-03932458 , version 1 (10-01-2023)

Identifiants

  • HAL Id : hal-03932458 , version 1

Citer

Jessica Ou, Béatrice Louis, Vincent Nail, Laure Balasse, Ahlem Bouhlel, et al.. Pharmacokinetic analysis and modelling to optimize radiolabeled-dendrimers biodistribution. Recherche en Imagerie et Technologie pour la Santé (RITS), May 2022, Brest, France. ⟨hal-03932458⟩
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