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

Abstract

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 tritylbased 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 DMXAAamine, doxorubicin, and gemcitabine, and their release kinetics were studied. Hereafter, API release from CCPMs based on mPEGb-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.

Design, development and clinical translation of CriPec®-based core-crosslinked polymeric micelles

“…However, the 4-fold increased nanomedicine uptake did not translate into a 4fold increase in the amount of released docetaxel, indicating that linker-dependent kinetics may benefit from further optimisation. For example, utilization of trityl-based linkers are known to result in fast API release in acidic conditions [68]. Analogously, also other successful nanomedicines (e.g.…”

“…Moreover, substitution on ortho-and para-position of the trityl group allows API release kinetics to be further modulated depending on the substitution pattern (Fig. 2 D-F, [68]). This can be used to optimize the release of any API towards the desired release profile.…”

Polymeric Nanoparticles for Drug Delivery

“…Such linkages include: 1) ester derivatives such as acetals, N/O-aminals, , ortho -esters, borates, and β-thiopropionates; 2) C=N double bond derivatives such as hydrazones, oximes, and imines; 3) maleic amide derivatives including cis -aconityls and 2-propionic-3-methylmaleic anhydride (CDM); and 4) trityl-based protecting groups or linkers (Figure ). , When choosing a pH cleavable linker, it is important to consider the stability in physiological conditions (pH 7.4) as many linkers will have partial cleavage even at this pH. The rate of cleavage can often be tuned by modifying the substituents on the linkers .…”

Time-Separated Pulse Release–Activation of an Enzyme from Alginate–Polyethylenimine Hydrogels Using Electrochemically Generated Local pH Changes

“…For example, it is well-known that tumor tissues are acidified compared to the healthy biological microenvironment. 17 When modeling smart pH-triggered release systems, one should use pH-sensitive materials which can be based on liposomes, 16 microparticles, 18 nanoparticles, 15 materials modified with pH-sensitive linkers, 19 metal−organic frameworks, 20 and ionic synthetic or natural polymers. 21 One such naturally derived material is alginate, which is a biocompatible and biodegradable ionic polysaccharide made of residues of α-Lguluronic and β-D-mannuronic acids.…”