While 3-D tissue models have received increasing attention over the past several decades in the development of traditional anti-cancer therapies, their potential application for the evaluation of advanced drug delivery systems such as nanomedicines has been largely overlooked. In particular, new insight into drug resistance associated with the 3-D tumor microenvironment has called into question the validity of 2-D models for prediction of in vivo anti-tumor activity. In this work, a series of complementary assays was established for evaluating the in vitro efficacy of docetaxel (DTX) -loaded block copolymer micelles (BCM+DTX) and Taxotere® in 3-D multicellular tumor spheroid (MCTS) cultures. Spheroids were found to be significantly more resistant to treatment than monolayer cultures in a cell line dependent manner. Limitations in treatment efficacy were attributed to mechanisms of resistance associated with properties of the spheroid microenvironment. DTX-loaded micelles demonstrated greater therapeutic effect in both monolayer and spheroid cultures in comparison to Taxotere®. Overall, this work demonstrates the use of spheroids as a viable platform for the evaluation of nanomedicines in conditions which more closely reflect the in vivo tumor microenvironment relative to traditional monolayer cultures. By adaptation of traditional cell-based assays, spheroids have the potential to serve as intermediaries between traditional in vitro and in vivo models for high-throughput assessment of therapeutic candidates.
Docetaxel (DTX), a chemotherapeutic agent, was coupled to the hydrophobic block of poly(ethylene glycol)-b-poly(epsilon-caprolactone) (PEG-b-PCL) copolymers synthesized by metal free ring-opening polymerization. Synthesis of the copolymers and the copolymer-drug conjugate (PEG-b-PCL-DTX) were confirmed by (1)H NMR and GPC analyses. The PEG-b-PCL-DTX conjugates had a approximately 1:3 drug/copolymer ratio (w/w) and a low critical micelle concentration in aqueous solution (14 mg/L). Encapsulation of DTX in PEG-b-PCL-DTX micelles resulted in an 1840-fold increase in the aqueous solubility of the drug. Release of physically encapsulated DTX from PEG-b-PCL-DTX micelles was slower than drug release from PEG-b-PCL micelles due to the improved compatibility between DTX and the micelle core. Core-conjugated DTX was released over the course of one week indicating that PEG-b-PCL-DTX micelles have the capacity for sustained drug release in the absence of physically encapsulated drug. Importantly, conjugation of DTX to the core-forming block had a profound effect on the morphology of the copolymer aggregates.
We have developed a straightforward and efficient method of introducing radiopacity into Polyvinyl alcohol (PVA)-2-Acrylamido-2-methylpropane sulfonic acid (AMPS) hydrogel beads (DC Bead™) that are currently used in the clinic to treat liver malignancies. Coupling of 2,3,5-triiodobenzaldehyde to the PVA backbone of pre-formed beads yields a uniformly distributed level of iodine attached throughout the bead structure (~150 mg/mL) which is sufficient to be imaged under standard fluoroscopy and computed tomography (CT) imaging modalities used in treatment procedures (DC Bead LUMI™. Despite the chemical modification increasing the density of the beads to ~1.3 g/cm3 and the compressive modulus by two orders of magnitude, they remain easily suspended, handled and administered through standard microcatheters. As the core chemistry of DC Bead LUMI™ is the same as DC Bead™, it interacts with drugs using ion-exchange between sulfonic acid groups on the polymer and the positively charged amine groups of the drugs. Both doxorubicin (Dox) and irinotecan (Iri) elution kinetics for all bead sizes evaluated were within the parameters already investigated within the clinic for DC Bead™. Drug loading did not affect the radiopacity and there was a direct relationship between bead attenuation and Dox concentration. The ability (Dox)-loaded DC Bead LUMI™ to be visualized in vivo was demonstrated by the administration of into hepatic arteries of a VX2 tumor-bearing rabbit under fluoroscopy, followed by subsequent CT imaging.
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