In the case of DTXL (Figure ), beads of standard size were used to map 4 -5 heavy atoms, whereas small size beads were chosen to map groups of atoms in ring structures. Bonded terms were automatically assigned via the use of the pycgtool based on the consensus between bond, angle and dihedral distributions derived from coarse-grained and atomistic simulations of the molecule dissolved in octanol at 300K (Figure ). The resulting logPow for DTXL was estimated to be 4.4, which is close to the experimental value of 4.2. ). These results would suggest a stronger propensity of the PEG-DTXL prodrugs to accumulate at the PLGA -water interface, with PEG25-DTXL being more stable than PEG10-DTXL. This appears to be in line with previous reported observations for which homopolymers can act as surface active substances. Finally, OA-DTXL presents a slightly higher preference to stay in the matrix than free DTXL with a translocation free energy barrier Δ𝐺 # * of -75.3 kJ mol -1 (Figure ). Then, the aggregation propensity of the four molecules with the PLGA matrix was predicted at two different concentrations, namely 9 and 27 mol. As shown in Figure , OA-DTXL had a strong propensity to aggregate, in a concentration dependent manner. This behavior was not observed for the other three compounds DTXL, PEG10-DTXL and PEG25-DTXL, all of which were stable as monomers in the two tested configurations (Figure ). This result is not surprising considering that, PLGA particle to an aqueous solution are presented in Figure . For DTXL and its conjugates, amounts of drug released are examined in the first 72h (Figure ). Note that within this time frame, the release is mostly diffusion driven as the PLGA matrix is still intact. DTXL has the fastest experimental release kinetics, corresponding to 75 ± 5 % of drug released within the first 8h and reaching almost 90% release at 72h of incubation (Figure , yellow line). Not surprisingly therefore DTXL is associated with the smallest predicted polymer-solvent translocation free energy barrier (Figure ), returning a Δ𝐺 # * = -69.8 kJ mol -1 . The experimental release kinetics of PEG550-DTXL is slower than that of DTXL (Figure , cyan line), reaching a 55±1.8% of drug released in the first 8h. This agrees with a higher energy required for translocation, which is predicted to be Δ𝐺 # * = -76.9 kJ mol -1 (Figure ). Moving from a short to a long PEG configuration, the mobility of the conjugates decreases as well as its release rate. Indeed, the experimental release kinetics of PEG1k-DTXL (MW 1,000 Da) is even slower than that of PEG550-DTXL. It takes approximately 72h for releasing 52±1.4% of the loaded drug (Figure , blue line). Consistently, the predicted translocation free energy barrier Δ𝐺 # * is higher returning a value of Δ𝐺 # * = -90.7 kJ mol -1 (Figure ).