Nanoparticle drug loading as a design parameter to improve docetaxel pharmacokinetics and efficacy

Abstract

Nanoparticle (NP) drug loading is one of the key defining characteristics of a NP formulation. However, the effect of NP drug loading on therapeutic efficacy and pharmacokinetics has not been thoroughly evaluated. Herein, we characterized the efficacy, toxicity and pharmacokinetic properties of NP docetaxel formulations that have differential drug loading but are otherwise identical. Particle Replication in Non-wetting Templates (PRINT®), a soft-lithography fabrication technique, was used to formulate NPs with identical size, shape and surface chemistry, but with variable docetaxel loading. The lower weight loading (9%-NP) of docetaxel was found to have a superior pharmacokinetic profile and enhanced efficacy in a murine cancer model when compared to that of a higher docetaxel loading (20%-NP). The 9%-NP docetaxel increased plasma and tumor docetaxel exposure and reduced liver, spleen and lung exposure when compared to that of 20%-NP docetaxel.

“Combo” nanomedicine: Co-delivery of multi-modal therapeutics for efficient, targeted, and safe cancer therapy

“…4 are some examples of micro-and nano-sized delivery systems commonly used for co-delivery of therapeutic agents [154]. Drugs may be covalently conjugated to polymers or peptides, loaded into nanoparticles via nanoprecipitation, emulsion, solvent evaporation, or soft lithography [155]. Biodegradation of a carrier and diffusion are two processes directing drug release from a nanocarrier, with the release rate depending upon drug desorption and diffusion through the NP matrix/matrix erosion [156].…”

Nanotechnology-based drug delivery systems for treatment of oral cancer: a review

“…96,[100][101][102][103][104][105][106][107] The nanoparticles (NPs) are mainly prepared via the dispersion of preformed polymers, the polymerization of monomers, ionic gelation, or the coacervation of hydrophilic polymers, but other methods for their generation have also been reported, such as supercritical fluid technology and particle replication in non-wetting templates (PRINT ® ; DeSimone Lab, Chapel Hill, NC, USA). [108][109][110][111][112][113][114] NPs can improve the stability of drugs and control their targeted delivery, allowing for a constant and uniform concentration at the site of a lesion and facilitating drug extravasation into the tumor system, thus reducing side effects. [115][116][117] Damascelli et al evaluated the effectiveness of the intraarterial infusion of paclitaxel incorporated in NPs based on human albumin (albumin NPs) for use as induction chemotherapy before definitive advanced tongue cancer treatment.…”

Enhanced antitumor effects by docetaxel/LL37-loaded thermosensitive hydrogel nanoparticles in peritoneal carcinomatosis of colorectal cancer

“…30 CI ,1 represents synergistic cytotoxicity, CI =1 represents addictive cytotoxicity, and CI .1 represents antagonistic cytotoxicity. 31 cell-apoptosis assay HCT116 cells (5×10 5 ) were grown on coverslips placed into six-well plates and allowed to attach overnight, treated with 20 μg LL37, 2 μg Doc, or a combination thereof for 24 hours. Cells were fixed with cold methanol and acetic acid (3/1, v/v) at 4°C overnight and stained with terminal deoxynucleotidyl transferase deoxyuridine triphosphate nickend labeling (TUNEL) for 30 minutes in the dark, washed again in PBS, and finally mounted in mounting medium (80% glycerol in PBS).…”