# Docetaxel Administration via Novel Hierarchical Nanoparticle Reduces Proinflammatory Cytokine Levels in Prostate Cancer Cells

## TL;DR

A new nanoparticle-based delivery system for docetaxel reduces proinflammatory cytokines in prostate cancer cells, potentially improving treatment outcomes.

## Contribution

A novel hierarchical nanoparticle delivery system for docetaxel is shown to reduce proinflammatory signaling in docetaxel-resistant prostate cancer cells.

## Key findings

- LNCaP-Doc/R cells required 90-fold higher docetaxel concentrations for 50% cell killing compared to naive cells.
- Free docetaxel treatment increased proinflammatory cytokines like IFNγ, IL-1α, and RANTES by 2–5.75-fold compared to HNP-encapsulated docetaxel.
- HNP-encapsulated docetaxel reduced macrophage differentiation markers in co-cultured U937 monocytes compared to free docetaxel.

## Abstract

Docetaxel (Doc) resistance in prostate cancer (CaP) is linked to the secretion of proinflammatory cytokines, which facilitate interactions between tumor cells and macrophages, contributing to treatment resistance. This study developed a Doc-resistant CaP cell line (LNCaP-Doc/R) to investigate whether encapsulating Doc in a PLGA-Chitosan core-shell hierarchical nanoparticle (HNP-Doc) could reduce proinflammatory signaling. Results showed that LNCaP-Doc/R cells required significantly higher Doc concentrations for effective treatment. Cells treated with free Doc exhibited markedly higher levels of proinflammatory cytokines compared to those treated with HNP-Doc. Additionally, co-culturing LNCaP-Doc/R cells with monocytes revealed reduced macrophage differentiation markers when treated with HNP-Doc. These findings suggest that nanoparticle-encapsulated Doc can mitigate the proinflammatory response associated with resistance, potentially improving therapeutic outcomes in CaP treatment.

Background: Docetaxel (Doc) resistance in prostate cancer (CaP) patients is associated with the secretion of proinflammatory cytokines that induce an interaction between tumor cells and macrophages. Tumor cell-derived cytokines released in response to increased intracellular concentrations of Doc attract monocytes and macrophages to the tumor site and induce Doc resistance. Objectives: To generate Doc-resistant CaP cell line LNCaP-Doc/R and determine if we could modulate/reduce proinflammatory signals by administering Doc, encapsulated in a PLGA: Chitosan core-shell hierarchical nanoparticle (HNP-Doc) in the resistant and naive CaP Cells. Methods: LNCaP-Doc/R cells were generated by intermittent increasing concentration of Doc, proliferation, growth curve and cytotoxicity of Doc and HNP-Doc were evaluated followed by LNCaP and LNCaP-Doc/R (Doc resistant) CaP cells co-cultured with U937 monocytes with either free Doc or HNP-Doc encapsulated Doc, and various cytokine levels were measured in the conditioned media to assess the cytokine levels. Results: Our results show that LNCaP-Doc-R cells had slower growth in the lag phase, needed a 90-fold increase in Doc concentration to achieve 50% killing. Basal levels of cytokines secreted by LNCaP and LNCaP-Doc/R cells in response to free Doc and HNP-encapsulated Doc differed considerably, with free Doc-treated cells demonstrating, on average, 2–7-fold higher pro-inflammatory cytokine levels as compared to HNP-encapsulated Doc. The levels of pro-inflammatory cytokines, such as IFNγ, IL-1α, and RANTES, were increased ~2.38, ~2.75, and ~5.75-fold, respectively, in free Doc-treated CaP cells and were significantly lower when Doc was delivered via HNP. Further, LNCaP-Doc/R cells co-cultured with U937 had significantly lower markers of macrophage differentiation in response to HNP-encapsulated Doc treatment as opposed to free Doc treatment. Conclusions: Based on this analysis, we conclude that Doc treatment in vitro is associated with a proinflammatory response involving cytokines linked to macrophage recruitment and activation, with a lesser proinflammatory response with HNP-encapsulated Doc treatment.