Zinc-Phthalocyanine-Loaded Extracellular Vesicles Increase Efficacy and Selectivity of Photodynamic Therapy in Co-Culture and Preclinical Models of Colon Cancer.

Pablo Lara,Ferry Ossendorp,Luis J. Cruz,Ruben V. Huis in ‘t Veld,Alan B. Chan,Carla Jorquera-Cordero

doi:10.3390/pharmaceutics13101547

Abstract

Photodynamic therapy (PDT) is a promising and clinically approved method for the treatment of cancer. However, the efficacy of PDT is often limited by the poor selectivity and distribution of the photosensitizers (PS) toward the malignant tumors, resulting in prolonged periods of skin photosensitivity. In this work, we present a simple and straightforward strategy to increase the tumor distribution, selectivity, and efficacy of lipophilic PS zinc phthalocyanine (ZnPc) in colon cancer by their stabilization in purified, naturally secreted extracellular vesicles (EVs). The PS ZnPc was incorporated in EVs (EV-ZnPc) by a direct incubation strategy that did not affect size distribution or surface charge. By using co-culture models simulating a tumor microenvironment, we determined the preferential uptake of EV-ZnPc toward colon cancer cells when compared with macrophages and dendritic cells. We observed that PDT promoted total tumor cell death in normal and immune cells, but showed selectivity against cancer cells in co-culture models. In vivo assays showed that after a single intravenous or intratumoral injection, EV-ZnPc were able to target the tumor cells and strongly reduce tumor growth over 15 days. These data expose opportunities to enhance the potential and efficacy of PDT using simple non-synthetic strategies that might facilitate translation into clinical practice.

Highlights

PS are interesting therapeutic agents for cancer therapy as they have the ability to produce reactive oxygen species (ROS) upon external light irradiation, which can be used to locally destroy tumors in a process described as photodynamic therapy (PDT) [1]
Targeting extracellular vesicles (EVs) were obtained from the culture media of melanoma B16F10 cells using a previously established protocol [15] that resulted in EVs with a typical vesicular shape and size close to 120 nm (Figure 1a,b)
We report on the development, characterization, and evaluation of EVZnPc for the treatment of colon cancer tumors

Summary

Introduction

PS are interesting therapeutic agents for cancer therapy as they have the ability to produce reactive oxygen species (ROS) upon external light irradiation, which can be used to locally destroy tumors in a process described as photodynamic therapy (PDT) [1]. PS combined with new technologies, such as improved endoscopic devices, are allowing an increased therapeutic efficacy, by enabling the irradiation of deep-seated tumors and producing ROS in small areas, greatly reducing side effects of conventional tumor therapeutics e.g., chemotherapy. Zinc phthalocyanine (ZnPc) is a promising photosensitizer for cancer therapy because of its minimal dark toxicity, excellent singlet oxygen quantum yield, and absorption within the therapeutic window that allows a favorable tissue penetration of the light used for photodynamic effect. Several authors have developed strategies using nanotechnology to encapsulate lipophilic PS and increase their efficacy in different cancer models.

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Conclusion