TY - JOUR
T1 - A New Class of Tunable Acid-Sensitive Linkers for Native Drug Release Based on the Trityl Protecting Group
AU - Timmers, Matt
AU - Weterings, Jimmy
AU - van Geijn, Michiel
AU - Bell, Roel
AU - Lenting, Peter E.
AU - Rijcken, Cristianne J.F.
AU - Vermonden, Tina
AU - Hennink, Wim E.
AU - Liskamp, Rob M.J.
PY - 2022/9/21
Y1 - 2022/9/21
N2 - 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 <1.0 to 5.0 h at pH 5.0 and
t
1/2 from 6.5 to >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 pK
a-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.
AB - 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 <1.0 to 5.0 h at pH 5.0 and
t
1/2 from 6.5 to >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 pK
a-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.
KW - Amines
KW - Delayed-Action Preparations/chemistry
KW - Doxorubicin/chemistry
KW - Drug Carriers/chemistry
KW - Drug Liberation
KW - Hydrogen-Ion Concentration
KW - Micelles
KW - Polyethylene Glycols/chemistry
KW - Polymers/chemistry
UR - http://www.scopus.com/inward/record.url?scp=85136691892&partnerID=8YFLogxK
U2 - 10.1021/acs.bioconjchem.2c00310
DO - 10.1021/acs.bioconjchem.2c00310
M3 - Article
C2 - 35979909
SN - 1043-1802
VL - 33
SP - 1707
EP - 1715
JO - Bioconjugate Chemistry
JF - Bioconjugate Chemistry
IS - 9
ER -