An in vivo mechanism for the reduced peripheral neurotoxicity of NK105: a paclitaxel-incorporating polymeric micellar nanoparticle formulation

Abstract

In our previous rodent studies, the paclitaxel (PTX)-incorporating polymeric micellar nanoparticle formulation NK105 had showed significantly stronger antitumor effects and reduced peripheral neurotoxicity than PTX dissolved in Cremophor ® EL and ethanol (PTX/CRE). Thus, to elucidate the mechanisms underlying reduced peripheral neurotoxicity due to NK105, we performed pharmacokinetic analyses of NK105 and PTX/CRE in rats. Among neural tissues, the highest PTX concentrations were found in the dorsal root ganglion (DRG). Moreover, exposure of DRG to PTX ( C max_PTX and AUC 0-inf._PTX ) in the NK105 group was almost half that in the PTX/CRE group, whereas exposure of sciatic and sural nerves was greater in the NK105 group than in the PTX/CRE group. In histopathological analyses, damage to DRG and both peripheral nerves was less in the NK105 group than in the PTX/CRE group. The consistency of these pharmacokinetic and histopathological data suggests that high levels of PTX in the DRG play an important role in the induction of peripheral neurotoxicity, and reduced distribution of PTX to the DRG of NK105-treated rats limits the ensuing peripheral neurotoxicity. In further analyses of PTX distribution to the DRG, Evans blue (Eb) was injected with BODIPY ® -labeled NK105 into rats, and Eb fluorescence was observed only in the DRG. Following injection, most Eb dye bound to albumin particles of ~8 nm and had penetrated the DRG. In contrast, BODIPY ® –NK105 particles of ~90 nm were not found in the DRG, suggesting differential penetration based on particle size. Because PTX also circulates as PTX–albumin particles of ~8 nm following injection of PTX/CRE, reduced peripheral neurotoxicity of NK105 may reflect exclusion from the DRG due to particle size, leading to reduced PTX levels in rat DRG (275).

Clinical Translation of Self‐Assembled Cancer Nanomedicines

“…NK105 significantly diminished neurotoxicity, as confirmed by both electrophysiological and morphological methods, exhibiting slightly increase in the caudal sensory nerve action potential (caudal SNAP) compared to control (i.e., glucose injection), as well as showing less incidence of degenerated myelinated nerve fibers in rats than that treated with PTX (Figure 2B,C). [ 52 ] A later in vivo study revealed that the mechanism for the reduced peripheral neurotoxicity of NK105 was the much lower concentration of PTX in the dorsal root ganglion (DRG) compared to free PTX, [ 55 ] which may be due to the large diameter of NK105 for extravasating the blood vessels of DRG.…”

Development of a Subcellular Semimechanism-Based Pharmacokinetic/Pharmacodynamic Model to Characterize Paclitaxel Effects Delivered by Polymeric Micelles

“…Therefore, some PTXloaded nanoparticle formulations have been developed and applied into clinic such as albumin-entrapped PTX (Abraxane™) and the polymeric micelle formulation (NK105 and Genexol-PM™). 18,19 The in vivo PK/PD models of PTX (including PTX-loaded nanoparticles) have been developed to relate the pharmacokinetics to the toxicity effect 2,20 or the magnitude of the pharmacologic effect. However, in vitro PK/PD models are rare studied and may be of great value, as it may facilitate the individualized chemotherapy of nanomedicine with the in vivo model.…”

Polymeric Micelles Based on Modified Glycol Chitosan for Paclitaxel Delivery: Preparation, Characterization and Evaluation

“…Among these formulations, polymeric micelles have been proven as promising drug delivery systems for PTX administration [ 9 , 10 ], because of their attractive characteristics, such as biocompatibility, high drug-loading content, small size (<200 nm) and propensity to evade scavenging by the mononuclear phagocyte system (MPS) [ 11 , 12 ]. Moreover, the nanoscale dimensions of polymeric micelles permit their selectively accumulation in tumor tissues due to the enhanced permeability and retention (EPR) effect, which is termed “passive targeting” [ 13 , 14 ].…”