# Synergistic Efficacy of WST11-VTP and P-Selectin-Targeted Nanotherapy in a Preclinical Prostate Cancer Model

## TL;DR

This study shows that combining photodynamic therapy with drug-loaded nanoparticles improves prostate cancer treatment in mice by increasing tumor control and survival.

## Contribution

The novel approach combines VTP with P-selectin-targeted nanodrugs, leveraging VTP-induced inflammation to enhance nanoparticle delivery and efficacy.

## Key findings

- Combination therapy significantly improved tumor control and recurrence-free survival compared to monotherapies.
- VTP increased nanoparticle concentration in tumors, validating the targeting mechanism.
- Nanodrug-VTP combinations outperformed radiotherapy in oncological outcomes.

## Abstract

This study introduces a new combination therapy to improve vascular-targeted photodynamic therapy (VTP) for prostate cancer. The main idea was that VTP-triggered inflammation increases P-selectin expression on tumor blood vessels, making it a target for drug-loaded nanoparticles. In a preclinical mouse model, WST11-VTP was combined with P-selectin-targeting nanoparticles carrying either paclitaxel or enzalutamide. The results showed a strong synergy, with the combination therapy significantly enhancing local tumor control and increasing recurrence-free survival compared to VTP or nanodrug monotherapies. In vivo imaging confirmed that VTP treatment resulted in a higher and more sustained concentration of nanoparticles within the tumor, validating the targeting mechanism. This approach, where VTP guides nanoparticle delivery, offers a promising strategy for future clinical trials in prostate cancer.

Objective: Radical therapies are associated with significant morbidity in patients with localized prostate cancer (PCa). While advances in nuclear magnetic resonance techniques have enabled the development of focal ablation procedures that can selectively destroy tumors, preserve the gland and surrounding structures, and minimize side effects, existing vascular-targeted photodynamic therapy (VTP) and nanodrug therapies often face limitations, such as recurrence and insufficient drug concentration at the tumor site. This study investigated a novel approach that combines VTP with systemic treatment using drug-loaded nanoparticles in a murine model, demonstrating substantial advancements beyond current monotherapies. Methods: SCID (severe combined immunodeficiency) mice were engrafted with androgen-sensitive prostate tumor cells (LNCaP-AR) and treated with a combination of VTP and two different drugs linked to fucoidan nanoparticles (Enzalutamide and Paclitaxel). Experiments were performed using different cohorts: the evaluation of oncological effect, the administration time and concentration of systemic therapy, a comparison of efficacy between VTP and radiotherapy, and the induction of the abscopal effect in untreated synchronous tumors. Results: The groups that received combination therapy showed better tumor control. After eight weeks, the recurrence-free survival rates were 87.5%, 62.5%, and 50% in the VTP + N-PAC, VTP + N-ENZ, and VTP monotherapy groups, respectively (p < 0.05). There was a significant difference in the intra-tumoral concentration of nanodrugs between the groups with combined treatment and monotherapy. After two weeks, the monotherapy groups showed almost total elimination of the drugs, whereas in the combined therapy groups, this concentration remained high, starting to decrease after three weeks (p < 0.05). Treatment with nanodrugs associated with VTP showed superior oncological benefits compared to radiotherapy alone or in combination with other therapies. The abscopal effect on synchronous tumors was not demonstrated with VTP alone or in combination with nanodrugs. Conclusions: Combining vascular photodynamic therapy with nanodrugs was highly effective in treating a prostate tumor model, leading to increased survival and a reduced risk of tumor recurrence. This approach significantly advances beyond existing VTP and nanodrug therapies by improving tumor control, ensuring sustained intra-tumoral drug concentration, and yielding superior oncological outcomes. Our results suggest that this therapy is a potential treatment option for prostate tumors treated with VTP in future clinical trials.