A New Class of Tunable Acid-Sensitive Linkers for Native Drug Release Based on the Trityl Protecting Group

Core-cross-linked polymeric micelles (CCPMs) are a promising nanoparticle platform due to favorable properties such as their long circulation and tumor disposition exploiting the enhanced permeability and retention (EPR) effect. Sustained release of covalently linked drugs from the hydrophobic core...

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Published in:Bioconjugate chemistry 2022-09, Vol.33 (9), p.1707-1715
Main Authors: Timmers, Matt, Weterings, Jimmy, van Geijn, Michiel, Bell, Roel, Lenting, Peter E., Rijcken, Cristianne J.F., Vermonden, Tina, Hennink, Wim E., Liskamp, Rob M.J.
Format: Article
Language:English
Subjects:
Amines
Biodegradability
Biodegradation
Block copolymers
Controlled release
Delayed-Action Preparations - chemistry
Doxorubicin
Doxorubicin - chemistry
Drug Carriers - chemistry
Drug delivery
Drug Liberation
Gemcitabine
Hydrogen-Ion Concentration
Hydrophobicity
Kinetics
Micelles
Nanoparticles
Permeability
pH effects
Polyethylene Glycols - chemistry
Polymers - chemistry
Protonation
Reaction mechanisms
Substitution reactions
Sustained release
Tumors
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Summary:Core-cross-linked polymeric micelles (CCPMs) are a promising nanoparticle platform due to favorable properties such as their long circulation and tumor disposition exploiting the enhanced permeability and retention (EPR) effect. Sustained release of covalently linked drugs from the hydrophobic core of the CCPM can be achieved by a biodegradable linker that connects the drug and the core. This study investigates the suitability of trityl-based linkers for the design of acid-triggered native active pharmaceutical ingredient (API) release from CCPMs. Trityl linker derivatives with different substituent patterns were synthesized and conjugated to model API compounds such as DMXAA-amine, doxorubicin, and gemcitabine, and their release kinetics were studied. Hereafter, API release from CCPMs based on mPEG-b-pHPMAmLac block copolymers was investigated. Variation of the trityl substitution pattern showed tunability of the API release rate from the trityl-based linker with t 1/2 varying from 24 h at pH 7.4, all at 37 °C. A clear difference in release kinetics was found between gemcitabine and doxorubicin, with gemcitabine showing no detectable release for 72 h at pH 5.0 and doxorubicin showing a t 1/2 of less than 1 h. Based on these findings, we show that the reaction mechanism of trityl deprotection plays an important role in the API release kinetics. The first step in this mechanism, which is protonation of the trityl-bound amine, is pKa-dependent, which explains the difference in release rate. In conclusion, acid-sensitive and tunable trityl linkers are highly promising for the design of linker–API conjugates and for their use in CCPMs.
ISSN:1043-1802
1520-4812
1520-4812
DOI:10.1021/acs.bioconjchem.2c00310