Polymer Nanoparticles Encased in a Cyclodextrin Complex Shell for Potential Site‐ and Sequence‐Specific Drug Release

Abstract

Time-staggered combination chemotherapy strategies show immense potential in cell culture systems, but fail to successfully translate clinically due to different routes of administration and disparate formulation parameters that preclude a specifi c order of drug presentation. A novel platform consisting of drug-containing PLGA polymer nanoparticles, stably fashioned with a shell composed of drug complexed with cationic cyclodextrin, capable of releasing drugs time-and sequence-specifi cally within tumors is designed. Morphological examination of nanoparticles measuring 150 nm highlight stable and distinct compartmentalization of model drugs, rhodamine and bodipy, within the core and shell, respectively. Sequential release is observed in vitro, owing to cyclodextrin shell displacement and subsequent sustained release of coreloaded drug, kinetics preserved in breast cancer cells following internalization. Importantly, time-staggered release is corroborated in a murine breast cancer model following intravenous administration. Precise control of drug release order, site-specifi cally, potentially opens novel avenues in polychemotherapy for synergy and chemosensitization strategies.

A multi-scale FE model for convective–diffusive drug transport within tumor and large vascular networks

“…We here emphasize that the goal of the paper was to formulate a computational framework for modeling complex problems such as convective-diffusive transport in organs or tumors, so that the presented results give basically a qualitative confirmation of the methodology. Quantitative verification of accuracy of models, which are incorporated into the methodology of this study, was partly given in our previous references [27,32,19,34], and the results are in agreement with general observations in experiments. We present two examples which demonstrate applicability of the developed computational model to two very different conditions, one is a tumor with extremely small dimensions and the other is an organ with an order-ofmagnitude larger dimensions and different material parameters.…”

“…can dominate the transport through the wall. This interaction on a molecular level may be incorporated into a continuum transport model by evaluation of the effective diffusion coefficients (or scaling functions) using MD procedures and a numerical homogenization (within a multiscale-hierarchical concept); such a multiscale model has been applied to various bioengineering problems [19,[27][28][29][30][31][32][33][34][35]. Briefly, the following steps are undertaken in formulating the multiscale model.…”

Mass partitioning effects in diffusion transport

“…Full details concerning fluorophore release, as in the case of nanoparticle fabrication and characterization can be found presented in [24]. Briefly, fluorophores were released into PBS and the concentration of both determined using a Synergy H4 Hybrid Reader and a previously established calibration curve.…”

Capillary collagen as the physical transport barrier in drug delivery to tumor microenvironment

“…Our recently developed computational multiscale transport theory and methodology enabled us to couple molecular and micro-scales for better prediction of drug transport. 18,27,28 We have used the systemic PK and characteristic pathology information to feed the transport models for the 3LL and 4T1 tumors. The kinetics of DOX accumulation showed that the DOX retention overcomes limitations of poorer diffusing DOX-loaded liposomes (PLD).…”