# Improving photodynamic therapy efficacy in bladder cancer using polymer micelle-encapsulated pheophorbide a

## TL;DR

A new method using micelles to deliver a photosensitizer improves photodynamic therapy for bladder cancer in lab models.

## Contribution

Micelle-encapsulated pheophorbide a shows enhanced photodynamic therapy efficacy in bladder cancer models.

## Key findings

- Encapsulated pheophorbide a showed higher phototoxicity in 2D bladder cancer cell cultures.
- Micelle delivery improved photosensitizer penetration and reduced spheroid viability in 3D models.
- Tissue-engineered 3D models support translational development of photodynamic therapy.

## Abstract

•Micelle encapsulation enhances pheophorbide a photodynamic efficacy in bladder cancer.•PEO–PCL micelles improve photosensitizer uptake and tissue penetration.•PDT efficacy is shown in both 2D cultures and 3D bladder cancer spheroids.•The tissue-engineered 3D model mimics human tumor bladder tissue and supports translational PDT development.•Results enable dual diagnostic–therapeutic use via existing cystoscopy tools.

Micelle encapsulation enhances pheophorbide a photodynamic efficacy in bladder cancer.

PEO–PCL micelles improve photosensitizer uptake and tissue penetration.

PDT efficacy is shown in both 2D cultures and 3D bladder cancer spheroids.

The tissue-engineered 3D model mimics human tumor bladder tissue and supports translational PDT development.

Results enable dual diagnostic–therapeutic use via existing cystoscopy tools.

Photodynamic diagnosis (PDD) is widely used in bladder cancer management, enabling fluorescence-guided detection of lesions through intravesical administration of photosensitizers such as hexaminolevulinate (Cysview®/Hexvix®). Building on this clinical framework, we explored photodynamic therapy (PDT) using pheophorbide a (pheo), a chlorophyll-based photosensitizer, encapsulated in self-assembled poly(ethylene oxide)-block-poly(ε-caprolactone) (PEO5000-PCL4000) micelles.

In vitro assays were performed on human bladder cancer cell lines, namely the grade 3 invasive T24 and the grade 1 SW780, in both 2D monolayers and 3D spheroid cultures. In 2D, encapsulated pheo showed higher phototoxicity (IC₅₀: 129 nM T24, 156 nM SW780), while free pheo exhibited negligible effects, preventing IC₅₀ determination. Two-photon microscopy confirmed that encapsulation markedly enhanced pheo penetration, especially in T24. SW780 spheroids exhibited tight epithelial features and low permeability, forming characteristic microbladder-like vesicles. PDT reduced viability in both T24 and SW780 3D models, with a significant advantage for encapsulated pheo at day 6 post-treatment in T24 spheroids. Preliminary exploration in human tissue-engineered bladder tumor substitutes demonstrated the feasibility for PDT assessment in complex 3D environments, warranting further study.

These findings support polymer nanocarrier-mediated pheo delivery as a promising therapeutic approach and pave the way for integrated diagnostic–therapeutic strategies using existing intravesical platforms.

Image, graphical abstract