Biodistribution and bioimaging studies of hybrid paclitaxel nanocrystals: Lessons learned of the EPR effect and image-guided drug delivery

Abstract

Paclitaxel (PTX) nanocrystals (200 nm) were produced by crystallization from solution. Antitumor efficacy and toxicity were examined through a survival study in a human HT-29 colon cancer xenograft murine model. The antitumor activity of the nanocrystal treatments was comparable with that by the conventional solubilization formulation (Taxol®), but yielded less toxicity as indicated by the result of survival study. Tritium-labeled PTX nanocrystals were further produced with a near infrared (NIR) fluorescent dye physically integrated in the crystal lattice. Biodistribution and tumor accumulation of the tritium-labeled PTX nanocrystals were determined immediately after intravenous administration and up to 48 hours by scintillation counting. Whole-body optical imaging of animals was concurrently carried out; fluorescent intensities were also measured from excised tumors and major organs of euthanized animals. It was found that drug accumulation in the tumor was less than 1% of 20 mg/kg intravenous dose. Qualitatively correlation was identified between the biodistribution determined by using tritium-labeled particles and that using optical imaging, but quantitative divergence existed. The divergent results suggest possible ways to improve the design of hybrid nanocrystals for cancer therapy and diagnosis. The study also raises questions of the general role of the enhanced permeability and retention (EPR) effect in tumor targeting and the effectiveness of bioimaging, specifically for hybrid nanocrystals, in tracking drug distribution and pharmacokinetics.

Albumin anchored docetaxel lipid nanoemulsion for improved targeting efficiency – preparation, characterization, cytotoxic, antitumor and in vivo imaging studies

“…The sequence of organ fluorescence intensity is Liver4Spleen4Lungs4Kidney 4Tumor4Heart. Similar type of tissue distribution was reported in the previous literature (Hollis et al, 2013;Liu et al, 2014). When ALNE was administered, the average radiance emitted by tumor was 3.04 times more than that of DLNE formulation.…”

Cellular Uptake Mechanism of Paclitaxel Nanocrystals Determined by Confocal Imaging and Kinetic Measurement

“…Our in vivo experiments have demonstrated that nanocrystal formulations of chemotherapeutic agents are capable of eliciting similar and better anticancer efficacy-compared with solubilized or encapsulated delivery systems-but exhibiting much reduced side effects (1,2). This may be contributed by the absence of helper chemicals that are used in the conventional formulations for solubilizing and/or encapsulating poorly soluble drugs (3)(4)(5)(6)(7).…”

“…Cellular Uptake Imaging of Nanocrystals KB cells were seeded in confocal petri dishes at a density of 2×10 5 cells/well and cultured for 24 h. After adhering to dish walls, the KB cells were incubated in FA-deficient RPMI 1640 medium with 100 μg/mL SRB-PTX-NCs at different durations (15, 30 min, 1, 2, and 3 h) or incubated for 3 h with the concentration of the nanocrystals varied (1,5,25, and 100 μg/mL). Additionally, the KB cells were incubated for 3 h in FA-deficient RPMI1640 medium with 100 μg/mL bare or surface-modified SRB-PTX-NCs (PEG-Dp-SRB-PTX-NCs, FA-PEG-Dp-SRB-PTX-NCs, PEG-SRB-PTX-NCs, FA-PEG-SRB-PTX-NCs, F 127 -SRB-PTX-NCs, and F 68 -SRB-PTX-NCs).…”

“…Importantly, nanocrystals are physically stable-albeit possible particle aggregation, which can be remedied or minimized by surface coating with surfactants-and unlikely to undergo drastic phase transition and structural change. Our recent study of paclitaxel nanocrystals (PTX-NCs) showed that the delivery system had similar but extended tumor accumulation with Taxol®, possibly due to the localization of drug nanocrystals (1). In addition, it was observed that more than 40% of injected nanocrystals were taken up by liver, considerably surpassing that by Taxol.…”

In vivo pharmacokinetics, biodistribution and antitumor effect of paclitaxel-loaded micelles based on α-tocopherol succinate-modified chitosan

“…This suggested that the micelles were sequestered by the macrophage phagocytic system (MPS) within few minutes of intravenous administration. The liver may temporarily act as a depot site of the drug and release the drug back into the systemic circulation, which could prolong the retention time of PTX (Hollis et al, 2013). Specially, for cancer therapy, it is important to reduce drug accumulation in the key organs, such as the heart and kidney, to avoid or minimize systemic side effects.…”