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. 2019 Jun 10:303:109-116.
doi: 10.1016/j.jconrel.2019.04.013. Epub 2019 Apr 11.

Prevention of paclitaxel-induced neuropathy by formulation approach

Xiaowei Zang  1 , Jong Bong Lee  1 , Kiran Deshpande  1 , Olga B Garbuzenko  1 , Tamara Minko  1 , Leonid Kagan  2
Affiliations

Prevention of paclitaxel-induced neuropathy by formulation approach

Xiaowei Zang et al. J Control Release. .

Abstract

Chemotherapy-induced peripheral neuropathy (CIPN) is a major adverse effect of paclitaxel. Several liposome-based products have been approved and demonstrated superior efficacy and safety profiles for other drugs. The first objective of this work was to evaluate the effect of liposome formulation of paclitaxel (L-PTX) on neurotoxicity in-vitro and in-vivo in comparison to the standard Taxol® formulation. The second aim was to investigate the effect of formulation on paclitaxel biodistribution following intravenous administration in an animal model. Free paclitaxel was toxic to cell of neuronal origin (IC50 = 18.4 μg/mL) at a lower concentration than to lung cancer cells (IC50 = 59.1 μg/mL), and L-PTX demonstrated a comparable toxicity in both cell lines (IC50 = 31.8 and 33.7 μg/mL). Administration of L-PTX at 2 mg/kg per dose for a total of 4 doses on day 0, 2, 4, and 6 to rats did not result in increased sensitivity in response to mechanical or thermal stimulation of hind paws, in comparison to Taxol® administration at the same dose level that resulted in neuropathy. Paclitaxel biodisposition was evaluated for two formulations in plasma, liver, lung, brain, spinal cord, skin and muscle of rats after single intravenous dose at 6 mg/kg. The exposure to paclitaxel in brain, spinal cord, muscle, and skin was lower in the L-PTX group compared to Taxol® group. PEGylated liposomes containing paclitaxel were successfully developed and demonstrated reduced neurotoxicity in-vitro in neuronal cells and prevented development of peripheral neuropathy in-vivo. This proof of concept study showed that formulation in nanoparticles is a promising approach for reducing (or preventing) neurotoxicity caused by cancer drugs.

Keywords: Biodistribution; Chemotherapy-induced peripheral neuropathy; Formulation; Liposomes; Nanoparticles; Neurotoxicity; Paclitaxel.

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Figures

Figure 1.
Figure 1.
Cell viability (CellTiter-Fluor™ assay) after incubation with various concentrations of L-PTX formulation and paclitaxel solution for 24 hours a) lung cancer cell line A549 and b) neuroblastoma cell line SH-SY5Y from 0.1 –100 μg/mL. Data are shown as mean ± SD (n=3). Lines are fitted curves.
Figure 2.
Figure 2.
a) Threshold for withdrawal in response to mechanical stimulation to the plantar surface of hind paw (using Ugo Basile dynamic plantar aesthesiometer) before and after tail vein injection of L-PTX or Taxol® at 2 mg/kg for 4 times (n = 10 each group). Statistically significant difference between treatment groups (* p < 0.05), and before and after Taxol® treatment (# – the first day that the significance (p < 0.05) vs. baseline was reached). Arrows indicate days of drug administration. b) Changes to the mechanical sensitivity threshold and animal body weight in a group without drug administration. Data are shown as mean ± SD (n=10).
Figure 3.
Figure 3.
Response time to thermal stimulation to the plantar surface of hind paw (using Ugo Basile Hargreaves apparatus) before and after injection of L-PTX or Taxol® at 2 mg/kg for 4 times (n = 10 each group). Statistically significant difference between treatment groups (* p # p < 0.05). Arrows indicate days of drug administration. Data are shown in mean ± SD.
Figure 4.
Figure 4.
Exposure to paclitaxel in the plasma, liver, lungs, brain, spinal cord, skin, and muscle, for Taxol® (filled symbols) and L-PTX (open symbols) groups after IV administration (tail vein) at a dose level of 6 mg/kg to rats. Data are presented as mean ± SD (n=3–4).
Figure 5.
Figure 5.
Ratio of paclitaxel concentrations in the liver, lungs, brain, spinal cord, skin, and muscle at 0.5 and 1 h in rats following IV bolus administration of Taxol® or L-PTX at 6 mg/kg (n=3–4).
Figure 6.
Figure 6.
Observed paclitaxel tissue distribution (open symbols) after IV administration of Taxol® 6 mg/kg overlaid with predictions generated using previously developed physiologically-based pharmacokinetic model (1) (dotted lines) for plasma, liver, lungs, skin, and muscle tissues. In the model, skin and muscle were lumped into a ‘remainder’ compartment; the simulated line on skin/muscle panel represents a profile for the ‘remainder’ compartment. Symbols represent experimental mean data obtained in this study (n=3–4).
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