Computational Prodrug Design Methodology for Liposome Formulability Enhancement of Small-Molecule APIs

Result code in IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F60461373%3A22340%2F23%3A43926679" target="_blank" >RIV/60461373:22340/23:43926679 - isvavai.cz</a>

Alternative codes found

RIV/61989592:15310/23:73620397

Result on the web

<a href="https://doi.org/10.1021/acs.molpharmaceut.2c01078" target="_blank" >https://doi.org/10.1021/acs.molpharmaceut.2c01078</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1021/acs.molpharmaceut.2c01078" target="_blank" >10.1021/acs.molpharmaceut.2c01078</a>

Result language

angličtina

Original language name

Computational Prodrug Design Methodology for Liposome Formulability Enhancement of Small-Molecule APIs

Original language description

Encapsulation into liposomes is a formulation strategy that can improve efficacy and reduce side effects of active pharmaceutical ingredients (APIs) that exhibit poor biodistribution or pharmacokinetics when administered alone. However, many APIs are unsuitable for liposomal formulations intended for parenteral administration due to their inherent physicochemical properties─lipid bilayer permeability and water-lipid equilibrium partitioning coefficient. Too high permeability results in premature leakage from liposomes, while too low permeability means the API is not able to pass across biological barriers. There are several options for solving this issue: (i) change of the lipid bilayer composition, (ii) addition of a permeability enhancer, or (iii) modification of the chemical structure of the API to design a prodrug. The latter approach was taken in the present work, and the effect of small changes in the molecular structure of the API on its permeation rate across a lipidic bilayer was systematically explored utilizing computer simulations. An in silico methodology for prodrug design based on the COSMOperm approach has been proposed and applied to four APIs (abiraterone, cytarabine, 5-fluorouracil, and paliperidone). It is shown that the addition of aliphatic hydrocarbon chains via ester or amide bonds can render the molecule more lipophilic and increase its permeability by approximately 1 order of magnitude for each 2 carbon atoms added, while the formation of fructose adducts can provide a more hydrophilic character to the molecule and reduce its lipid partitioning. While partitioning was found to depend only on the size and type of the added group, permeability was found to depend also on the added group location. Overall, it has been shown that both permeability and lipid partitioning coefficient can be systematically shifted into the desired liposome formulability window by appropriate group contributions to the parental drug. This can significantly increase the portfolio of APIs for which liposome or lipid nanoparticle formulations become feasible. © 2023 The Authors. Published by American Chemical Society.

Czech name

—

Czech description

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Type

J_imp - Article in a specialist periodical, which is included in the Web of Science database

CEP classification

—

OECD FORD branch

10403 - Physical chemistry

Project

Result was created during the realization of more than one project. More information in the Projects tab.

Continuities

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Publication year

2023

Confidentiality

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Name of the periodical

Molecular Pharmaceutics

ISSN

1543-8384

e-ISSN

—

Volume of the periodical

20

Issue of the periodical within the volume

4

Country of publishing house

US - UNITED STATES

Number of pages

9

Pages from-to

2119-2127

UT code for WoS article

000962218300001

EID of the result in the Scopus database

2-s2.0-85151238864