TY  - JOUR
A1  - Brunacci, Nadia
A1  - Neffe, Axel T.
A1  - Wischke, Christian
A1  - Naolou, Toufik
A1  - Nöchel, Ulrich
A1  - Lendlein, Andreas
T1  - Oligodepsipeptide (nano)carriers
BT  - computational design and analysis of enhanced drug loading
JF  - Journal of controlled release
N2  - High drug loads of nanoparticles are essential to efficiently provide a desired dosage in the required timeframe, however, these conditions may not be reached with so far established degradable matrices. Our conceptual approach for increasing the drug load is based on strengthening the affinity between drug and matrix in combination with stabilizing drug-matrix-hybrids through strong intermolecular matrix interactions. Here, a method for designing such complex drug-matrix hybrids is introduced employing computational methods (molecular dynamics and docking) as well as experimental studies (affinity, drug loading and distribution, drug release from films and nanoparticles). As model system, dexamethasone (DXM), relevant for the treatment of inflammatory diseases, in combination with poly[(rac-lactide)-co-glycolide] (PLGA) as standard degradable matrix or oligo[(3-(S)-sec-butyl) morpholine-2,5-dione] diol (OBMD) as matrix with hypothesized stronger interaction with DXM were investigated. Docking studies predicted higher affinity of DXM to OBMD than PLGA and displayed amide bond participation in hydrogen bonding with OBMD. Experimental investigations on films and nanoparticles, i.e. matrices of different shapes and sizes, confirmed this phenomenon as shown e.g. by a similar to 10 times higher solid state solubility of DXM in OBMD than in PLGA. DXM-loaded particles of similar to 150 nm prepared by nanoprecipitation in aqueous environment had a drug loading (DL) up to 16 times higher when employing OBMD as matrix compared to PLGA carriers due to enhanced drug retention in the OBMD phase. Importantly, drug relase periods were not altered as the release from films and particles was mainly ruled by the diffusion length as well as matrix degradation rather than the matrix type, which can be assigned to water diffusing into the matrix and breaking up of drug-matrix hydrogen bonds. Overall, the presented design and fabrication scheme showed predictive power and might universally enable the screening of drug/matrix interactions particularly to expand the oligodepsipeptide platform technology, e.g. by varying the depsipeptide side chains, for drug carrier and release systems.
KW  - Oligodepsipeptide
KW  - Drug loading
KW  - Nanoparticles
KW  - Docking study
KW  - Molecular interaction design
Y1  - 2019
U6  - https://doi.org/10.1016/j.jconrel.2019.03.004
SN  - 0168-3659
SN  - 1873-4995
VL  - 301
SP  - 146
EP  - 156
PB  - Elsevier
CY  - Amsterdam
ER  -