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Physiologically Based Pharmacokinetic Modeling of Fluorescently Labeled Block Copolymer Nanoparticles for Controlled Drug Delivery in Leukemia Therapy.

ABSTRACT: A physiologically based pharmacokinetic (PBPK) model was developed that describes the concentration and biodistribution of fluorescently labeled nanoparticles in mice used for the controlled delivery of dexamethasone in acute lymphoblastic leukemia (ALL) therapy. The simulated data showed initial spikes in nanoparticle concentration in the liver, spleen, and kidneys, whereas concentration in plasma decreased rapidly. These simulation results were consistent with previously published in vivo data. At shorter time scales, the simulated data predicted decrease of nanoparticles from plasma with concomitant increase in the liver, spleen, and kidneys before decaying at longer timepoints. Interestingly, the simulated data predicted an unaccounted accumulation of about 50% of the injected dose of nanoparticles. Incorporation of an additional compartment into the model justified the presence of unaccounted nanoparticles in this compartment. Our results suggest that the proposed PBPK model can be an excellent tool for prediction of optimal dose of nanoparticle-encapsulated drugs for cancer treatment.

SUBMITTER: Gilkey MJ

PROVIDER: S-EPMC4394613 | biostudies-literature | 2015 Mar

REPOSITORIES: biostudies-literature

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Physiologically Based Pharmacokinetic Modeling of Fluorescently Labeled Block Copolymer Nanoparticles for Controlled Drug Delivery in Leukemia Therapy.

Gilkey M J MJ Krishnan V V Scheetz L L Jia X X Rajasekaran A K AK Dhurjati P S PS

CPT: pharmacometrics & systems pharmacology 20150312 3

A physiologically based pharmacokinetic (PBPK) model was developed that describes the concentration and biodistribution of fluorescently labeled nanoparticles in mice used for the controlled delivery of dexamethasone in acute lymphoblastic leukemia (ALL) therapy. The simulated data showed initial spikes in nanoparticle concentration in the liver, spleen, and kidneys, whereas concentration in plasma decreased rapidly. These simulation results were consistent with previously published in vivo data ...[more]

PMID: 26225236

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Project description:IntroductionRadioimmunotherapy (RIT) with 90Y-labeled anti-CD66 antibody is used to selectively irradiate the red marrow (RM) before blood stem cell transplantation of acute leukemia patients. To calculate the activity to administer, time-integrated activity coefficients are required. These are estimated prior to therapy using gamma camera and serum measurements after injection of 111In labeled anti-CD66 antibody. Equal pre-therapeutic and therapeutic biodistributions are usually assumed to calculate the coefficients. However, additional measurements during therapy had shown that this assumption had to be abandoned. A physiologically based pharmacokinetic (PBPK) model was developed to allow the prediction of therapeutic time-integrated activity coefficients in eight patients.AimsThe aims of the study were to demonstrate using a larger patient group 1) the need to perform patient-specific dosimetry in 90Y-labeled anti-CD66 RIT, 2) that pre-therapeutic and therapeutic biodistributions differ, and most importantly 3) that this difference in biodistributions can be accurately predicted using a refined model.Materials and methodsTwo new PBPK models were developed considering fully, half and non-immunoreactive antibodies and constraints for estimating the RM antigen number. Both models were fitted to gamma camera and serum measurements of 27 patients. Akaike weights were used for model averaging. Time-integrated activity coefficients for total body, liver, spleen, RM and serum were calculated. Model-based predictions of the serum biokinetics during therapy were compared to actual measurements.ResultsVariability of the RM time-integrated activity coefficients ((37.3 ± 7.5) h) indicates the need for patient-specific dosimetry. The relative differences between pre-therapeutic and therapeutic serum time-activity curves were (-25 ± 16)%. The prediction accuracy of these differences using the refined PBPK models was (-3 ± 20)%.ConclusionIndividual treatment is needed due to biological differences between patients in RIT with 90Y-labeled anti-CD66 antibody. Differences in pre-therapeutic and therapeutic biokinetics are predominantly caused by different degrees of saturation due to different amounts of administered antibody. These differences could be predicted using the PBPK models.

Project description:In recent decades, drug delivery systems (DDSs) based on polymer nanoparticles have been explored due to their potential to deliver drugs with poor water solubility. Some of the limitations of nanoparticle-based DDSs can be overcome by developing an appropriate polymer prodrug. In this work, poly(NIPA)-b-poly(HMNPPA)-b-poly(PEGMA-stat-BA) was synthesized using reversible addition fragmentation chain transfer polymerization and Chlorambucil (Cbl), an anticancer drug, was conjugated to the copolymer via 3-(3-(hydroxymethyl)-4-nitrophenoxy)propyl acrylate (HMNPPA) units to prepare the prodrug. A few biotin acrylate (BA) units were also incorporated to bring potential targeting capability to the prodrug in the copolymer. This polymer prodrug formed spherical micellar nanoparticles in physiological conditions, which were characterized by dynamic light scattering and transmission electron microscopy measurements. The very low critical aggregation concentration (cac) (0.011 mg/mL) of the prodrug, as measured from Nile Red fluorescence, makes it stable against dilution. The polymer prodrug was shown to release Cbl on photoirradiation by soft UV (λ ≥ 365 nm) and laser (λ = 405 nm) light. The prodrug micellar nanoparticles were capable of encapsulating a second drug (doxorubicin, DOX) in their hydrophobic core. On photoirradiation with UV and laser light of the DOX-loaded nanoparticles, both Cbl and DOX were released. Light-induced breaking of photolabile ester bond resulted in the release of Cbl and caused disruption of the nanoparticles facilitating release of DOX. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay confirmed the nontoxicity of the polymers and effectiveness of the dual drug-loaded micellar nanoparticles toward cancer cells. Confocal microscopy results showed a better cellular internalization capability of the DOX-loaded nanoparticles in cancer cells, possibly due to the presence of cancer cell targeting biotin molecules in the polymer. This new photoresponsive potentially biocompatible and cancer cell-targeted polymer prodrug may be useful for delivery of single and/or multiple hydrophobic drugs.

Project description:Although there has been substantial progress in the research field of gene delivery, there are some challenges remaining, e.g. there are still cell types such as primary cells and suspension cells (immune cells) known to be difficult to transfect. Cationic polymers have gained increasing attention due to their ability to bind, condense and mask genetic material, being amenable to scale up and highly variable in their composition. In addition, they can be combined with further monomers exhibiting desired biological and chemical properties, such as antioxidative, pH- and redox-responsive or biocompatible features. By introduction of hydrophobic monomers, in particular as block copolymers, cationic micelles can be formed possessing an improved chance of transfection in otherwise challenging cells. In this study, the antioxidant biomolecule lipoic acid, which can also be used as crosslinker, was incorporated into the hydrophobic block of a diblock copolymer, poly{[2-(dimethylamino)ethyl methacrylate]101-b-[n-(butyl methacrylate)124-co-(lipoic acid methacrylate)22]} (P(DMAEMA101-b-[nBMA124-co-LAMA22])), synthesized by RAFT polymerization and assembled into micelles (LAMA-mic). These micelles were investigated regarding their pDNA binding, cytotoxicity mechanisms and transfection efficiency in K-562 and HEK293T cells, the former representing a difficult to transfect, suspension leukemia cell line. The LAMA-mic exhibited low cytotoxicity at applied concentrations but demonstrated superior transfection efficiency in HEK293T and especially K-562 cells. In-depth studies on the transfection mechanism revealed that transfection efficiency in K-562 cells does not depend on the specific oncogenic fusion gene BCR-ABL alone. It is independent of the cellular uptake of polymer-pDNA complexes but correlates with the endosomal escape of the LAMA-mic. A comparison of the transfection efficiency of the LAMA-mic with structurally comparable micelles without lipoic acid showed that lipoic acid is not solely responsible for the superior transfection efficiency of the LAMA-mic. More likely, a synergistic effect of the antioxidative lipoic acid and the micellar architecture was identified. Therefore, the incorporation of lipoic acid into the core of hydrophobic-cationic micelles represents a promising tailor-made transfer strategy, which can potentially be beneficial for other difficult to transfect cell types.

Dataset Information

Physiologically Based Pharmacokinetic Modeling of Fluorescently Labeled Block Copolymer Nanoparticles for Controlled Drug Delivery in Leukemia Therapy.

Publications

Physiologically Based Pharmacokinetic Modeling of Fluorescently Labeled Block Copolymer Nanoparticles for Controlled Drug Delivery in Leukemia Therapy.

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