"Introduction. Photodynamic therapy (PDT), an anti-cancer therapeutic approach based on the selective activation by light of photosensitive molecules called ""photosensitizers"" 1, is promising in the context of bladder cancer treatment. This is due to the accessibility of the tumors in the bladder cavity for both instillation of photosensitizer and light irradiation 2. A main drawback of photosensitizers is their low aqueous solubility that results in their aggregation and which lower the PDT efficacy. In order to improve their delivery and therapeutic efficacy, we propose to encapsulate photosensitizers in nanocarriers based on self-assembled polymer micelles 3. We aimed at understanding and quantifying how photosensitizers, whether or not vectorised in polymeric nano-objects, behave at bladder tissue scale in the perspective of proposing a safe, efficient and easy to handle treatment against human bladder cancer.
Methodology. In the context of this work, pheophorbide a was used as model photosensitizer 4. It was encapsulated within self-assembled polymer micelles based on poly(ethylene oxide)-block-poly(ɛ-caprolactone) PEO-PCL, an amphiphilic block copolymer 5. Efficacy of the PDT was tested on a panel of bladder tumor cell lines of different degree of aggressiveness, namely T24, SW780, SW1710 and MgHu3. Moreover, the treatment was performed in tumor models of increasing complexity: 2D monolayer, 3D tumor spheroids and human cancerous bladder substitutes produced by tissue engineering using the self-assembly approach 6.
Results. The encapsulation of pheophorbide a in PEO-PCL micelles resulted in an improvement of PDT efficiency in both 2D monolayer and 3D tumor spheroids, yielding a 10-fold improvement of the therapeutic index for the same pheophorbide concentration. Two-photon microscopy observations revealed increased tissue penetration of the pheophorbide within the tumor spheroids when it was encapsulated within micelles compared to its free form. Experiments in human 3D bladder cancer substitutes are still ongoing and will help to better describe tumor cell response to PDT within a complex microenvironment.
Conclusion. Vectorization of hydrophobic photosensitizers undoubtedly increases its diffusion capacity within tumor tissue, ensuring a better therapeutic efficacy when stimulated with light during photodynamic therapy.
1. Juarranz, Á., Gilaberte, Y., and González, S. Photodynamic Therapy (PDT) in Oncology. Cancers. 12, 2020.
2. Yun, S.H., and Kwok, S.J.J. Light in diagnosis, therapy and surgery. Nat Biomed Eng. 2017/01/10 ed. 1, 0008, 2017.
3. Demazeau, M., Gibot, L., Mingotaud, A.-F., Vicendo, P., Roux, C., and Lonetti, B. Rational design of block copolymer self-assemblies in photodynamic therapy. Beilstein J Nanotechnol. 11, 180, 2020.
4. Xodo, L., Rapozzi, V., Zacchigna, M., Drioli, S., and Zorzet, S. The chlorophyll catabolite pheophorbide a as a photosensitizer for the photodynamic therapy. Curr Med Chem. 19, 799, 2012.
5. Gibot, L., Lemelle, A., Till, U., Moukarzel, B., Mingotaud, A.-F., Pimienta, V., et al. Polymeric Micelles Encapsulating Photosensitizer: Structure/Photodynamic Therapy Efficiency Relation. Biomacromolecules. 15, 1443, 2014.
6. Goulet, C.R., Bernard, G., Chabaud, S., Couture, A., Langlois, A., Neveu, B., et al. Tissue-engineered human 3D model of bladder cancer for invasion study and drug discovery. Biomaterials. Elsevier, 145, 233, 2017."