Polyester nanoparticle‐encapsulated paclitaxel mitigates paclitaxel‐induced peripheral neuropathy

다국어 초록 (Multilingual Abstract)

Chemotherapy utilizing cytotoxic drugs such as paclitaxel (PTX) is still a major therapeutic approach to treat both localized and metastasized cancers. Unlike traditional regimens, where PTX is administered at the maximum tolerated dose, alternative regimen like metronomic dosing are proving beneficial, where PTX is administered more frequently and in much lower doses exploring anti‐angiogenic and immunomodulatory effects. However, PTX‐induced peripheral neuropathy (PIPN) and lack of non‐invasive dosage forms of PTX are major roadblocks for the successful implementation of metronomic regimens. Given the success of polyester nanoparticle drug delivery, our aim was to explore the potential of nanoparticle‐encapsulated paclitaxel (nPTX) in alleviating PIPN in an experimental rat model. In this study, rats were injected intraperitoneal with 2 mg/kg body weight of PTX or nPTX on four alternate days and PIPN was characterized using behavioral assessments, histology and immunohistochemistry. PIPN was revealed by a significant decrease in the tactile sensitivity and pressure pain threshold in PTX group compared to the nPTX group over a 16‐day study period. The behavior data was supported by histological assessments, where PTX group showed a higher degree of dorsal root ganglion (DRG) degeneration and a significant reduction in motor neurons compared to nPTX group. Further, immunofluorescence data reveals increase in the density of neuronal marker β‐tubulin‐III (TUBB3), reduced TUNEL positive cells and increase in high molecular weight neurofilament (NFH) in spinal cord, DRG and sciatic nerve for nPTX group. Therefore, this work has important implications in improving risk‐benefit profile of PTX, paving way for metronomic regimens.







The characteristics of nPTX used in this present study. a) Table showing the formulation characteristics of different batches b) Representative dynamic light scattering particle size distribution profile and c) Representative scanning electron micrograph of nPTX. *The difference in the entrapment numbers is not the reproducibility issue, but different volume of the suspension used in the vial for freeze drying.








nPTX reduces the pain hypersensitivity of rats compared to those treated with PTX. a) Tactile threshold and b) Pressure threshold, time course of the effect of intraperitoneal injections of PTX and nPTX at 2mg/kg administered as indicated by arrows on x‐axis. BL is baseline data. We used same rats in a & b experiments. *p < 0.05, **p < 0.01, ***p < 0.001 and ****p < 0.0001 comparisons were made between PTX vs nPTX; two‐way analysis of variance followed by Tukey's multiple comparisons test (n=8).








nPTX prevents dorsal root ganglion (DRG) degeneration. a) H&E‐stained sections were prepared from the DRG nerve at the end of the study. b) PTX group showed degeneration of neurons presenting significantly low in DRG numbers compared to nPTX group indicated with bright red arrowheads. c) PTX levels in DRG, PTX and nPTX groups are not significant. ***p < 0.001 comparisons were made between PTX vs nPTX; two‐way analysis of variance followed by Tukey's multiple comparisons test.








nPTX increase motor neuron survival in spinal cord (SC) region. a) Representative images of ventral root horn spinal cords of PTX and nPTX treated rats. b) SC motor neuron counts significantly decreased in PTX groups compared to nPTX. Images were acquired at 10 and 40x original magnification. c) PTX levels in SC, PTX and nPTX groups are not significant. The PTX levels between DRG and SC are about 100 orders of magnitude, presumably due to the deficiency in blood‐nerve barrier in the former.

The characteristics of nPTX used in this present study. a) Table showing the formulation characteristics of different batches b) Representative dynamic light scattering particle size distribution profile and c) Representative scanning electron micrograph of nPTX. *The difference in the entrapment numbers is not the reproducibility issue, but different volume of the suspension used in the vial for freeze drying.
nPTX reduces the pain hypersensitivity of rats compared to those treated with PTX. a) Tactile threshold and b) Pressure threshold, time course of the effect of intraperitoneal injections of PTX and nPTX at 2mg/kg administered as indicated by arrows on x‐axis. BL is baseline data. We used same rats in a & b experiments. *p < 0.05, **p < 0.01, ***p < 0.001 and ****p < 0.0001 comparisons were made between PTX vs nPTX; two‐way analysis of variance followed by Tukey's multiple comparisons test (n=8).
nPTX prevents dorsal root ganglion (DRG) degeneration. a) H&E‐stained sections were prepared from the DRG nerve at the end of the study. b) PTX group showed degeneration of neurons presenting significantly low in DRG numbers compared to nPTX group indicated with bright red arrowheads. c) PTX levels in DRG, PTX and nPTX groups are not significant. ***p < 0.001 comparisons were made between PTX vs nPTX; two‐way analysis of variance followed by Tukey's multiple comparisons test.
nPTX increase motor neuron survival in spinal cord (SC) region. a) Representative images of ventral root horn spinal cords of PTX and nPTX treated rats. b) SC motor neuron counts significantly decreased in PTX groups compared to nPTX. Images were acquired at 10 and 40x original magnification. c) PTX levels in SC, PTX and nPTX groups are not significant. The PTX levels between DRG and SC are about 100 orders of magnitude, presumably due to the deficiency in blood‐nerve barrier in the former.
This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.