Plasma, tumor and tissue pharmacokinetics of Docetaxel delivered via nanoparticles of different sizes and shapes in mice bearing SKOV-3 human ovarian carcinoma xenograft

Abstract

The particle fabrication technique PRINT® was used to fabricate monodisperse size and shape specific poly(lactide-co-glycolide) particles loaded with the chemotherapeutic Docetaxel. The pharmacokinetics of two cylindrical shaped particles with diameter=80nm; height=320nm (PRINT-Doc-80×320) and d=200nm; h=200nm (PRINT-Doc-200×200) were compared to Docetaxel in mice bearing human ovarian carcinoma SKOV-3 flank xenografts. The Docetaxel plasma exposure was ~20-fold higher for both particles compared to docetaxel. Additionally, the volume of distribution (Vd) of Docetaxel in PRINT formulations was ~18-fold (PRINT-Doc-80×320) and ~33-fold (PRINT-Doc-200×200) lower than Docetaxel. The prolonged duration of Docetaxel in plasma when dosed with PRINT formulations subsequently lead to increased tumor exposure of Docetaxel from 0-168 hours (~53% higher for PRINT-Doc-80×320 and ~76% higher for PRINT-Doc-200×200 particles). PRINT-Doc-80×320 had lower exposures in the liver, spleen and lung compared with PRINT-Doc-200×200. Thus, the use of particles with smaller feature size may be preferred to decrease clearance by organs of the mononuclear phagocyte system.

Using shape effects to target antibody-coated nanoparticles to lung and brain endothelium

“…Other nonspherical particles, particularly discoidal particles, have been shown to exhibit up to fivefold higher tumor accumulation at a micro-and nanoscale compared with spherical particles of the same size (44). At the nanoscale, rod-shaped particles have been shown to exhibit higher cellular internalization (38) and such particles have been shown to exhibit excellent targeting in tumor xenografts (45). Iron oxide nanoworms and gold nanorods have been shown to induce higher tumor accumulation (46,47), and gold nanorods have been shown to exhibit reduced macrophage clearance (48).…”

Nanoparticle clearance is governed by Th1/Th2 immunity and strain background

“…In most studies, nanoparticle PK is determined by blood draws at specific time points after injection, combined with appropriate assays for determining the particle concentration in the blood (39,40). This method has the advantage of directly measuring the…”

Efficacy and Pharmacokinetics of a Modified acid-labile docetaxel-PRINT ® Nanoparticle Formulation Against non-small-cell Lung Cancer Brain Metastases

“…Encapsulated cargo has a different pharmacodynamic profile than free drug and takes on the pharmacokinetics of its carrier. This results in increased systemic half-life of the drug, changes in the drug tissue distribution and increased drug-tumor exposure with less systemic toxicity [6,9,13,17]. In this manner, nanoparticle encapsulation generates a prodrug of the free drug cargo [6].…”

“…Generally, all data analysis and statistical methods were performed as previously described [6,13,14,17].…”

“…A single step reaction of docetaxel with chlorodimethylethylsilane was performed to generate the C2′ alcohol of taxane, the silyl ether docetaxel prodrug C2, as previously described [13]. PRINT-C2-docetaxel and PRINT-docetaxel nanoparticles were fabricated as previously described, to form the same sized cylindrical particles of PLGA polymer with a diameter of 80 nm and height of 320 nm, with similar drug loading [13,[15][16][17][18]. Briefly, a thin film of PLGA and Docetaxel or C2-Docetaxel was deposited on a 6″ × 12″ sheet of PET (poly[ethylene terephthalate]) by spreading 150 μl of a 10 mg/ml PLGA and 10 mg/ml docetaxel or C2-docetaxel chloroform solution using a # 5 Mayer Rod (R.D.…”