Release, Partitioning, and Conjugation Stability of Doxorubicin in Polymer Micelles Determined by Mechanistic Modeling

Abstract

Purpose To better understand the mechanistic parameters that govern drug release from polymer micelles with acid-labile linkers. Methods A mathematical model was developed to describe drug release from block copolymer micelles composed of a poly(ethylene glycol) shell and a poly(aspartate) core, modified with drug binding linkers for pH-controlled release [hydrazide (HYD), aminobenzoate-hydrazide (ABZ), or glycine-hydrazide (GLY)]. Doxorubicin (Dox) was conjugated to the block copolymers through acid-labile hydrazone bonds. The polymer drug conjugates were used to prepare three polymer micelles (HYD-M, ABZ-M, and GLY-M). Drug release studies were performed to identify the factors governing pH-sensitive release of Dox. The effect of prolonged storage of copolymer material on release kinetics was also observed. Results Biphasic drug release kinetics were observed for all three micelle formulations. The developed model was able to quantify observed release kinetics upon the inclusion of terms for unconjugated Dox and two populations of conjugated Dox. Micelle/water partitioning of Dox was also incorporated into the model and found significant in all micelles under neutral conditions but reduced under acidic conditions. The drug binding linker played a major role in drug release as the extent of Dox release at specific time intervals was greater at pH 5.0 than at pH 7.4 (HYD-M > ABZ-M > GLY-M). Mathematical modeling was also able correlate changes in release kinetics with the instability of the hydrazone conjugation of DOX during prolonged storage. Conclusion These results illustrate the potential utility of mechanistic modeling to better assess release characteristics intrinsic to a particular drug/nanoparticle system.

Polymer Nanoassemblies With solvato- and halo-fluorochromism for Drug Release Monitoring and Metastasis Imaging

“…Solvato-fluorochromic methods measure drugs remaining in the nanoparticle core, while HPLC methods measure drugs inside the nanoparticle core and drugs outside the core, which may be bound to polymers or remain in the aqueous environment [45]. Drugs bound to polymers or in solution are not expected to affect in vivo drug release rates, even though they can significantly affect HPLC measurements [46]. Although mechanistic modeling has been used to correct for these interactions in HPLC methods, solvato-fluorochromic methods provide a unique opportunity to directly measure drug release from the nanoparticle core during drug release measurements.…”

Modeling of Nanotherapy Response as a Function of the Tumor Microenvironment: Focus on Liver Metastasis

“…Traditional pharmacokinetics and pharmacodynamics (PK/PD) correlate efficacy of small molecule drugs with time-dependent changes in average bulk drug concentration at the site of action. However, it has been shown that these PK/PD methods often fail to predict efficacy of drug-loaded NV that control drug concentrations in vascular, interstitial and intracellular spaces of tumor ( Ponta and Bae, 2014 ; Ponta et al, 2015 ; Curtis et al, 2016b ). In addition, traditional analyses frequently simplify or rule out tumor physiology changing over time ( Khawar et al, 2015 ; Khalid et al, 2016 ).…”

Mechanistic model and analysis of doxorubicin release from liposomal formulations

“…In the empirical model above, the variables , , and , refer to the control factors of reservoir pH (7.0, 7.4, and 7.8), reservoir concentration of total ammonia (0, 50, and 100 mM), and the dilution factor of the liposomal suspension in the dialysis tube (8,16, and 24-fold), respectively. Regression was performed using Minitab v 16.1 software for all the constants (a i , b i , and c i ) in Eq.…”

“…[11,15,16,19] Drug transport kinetics across the dialysis membrane are likely to vary with the drug of interest in the study, either by having an increased or decreased rate of transport across the membrane, or because of processes associated with the equilibria and kinetics of drug binding to the dialysis membrane. The present study considered a mechanism in line with the latter scenario to describe DXR dialysis membrane transport.…”