Photocytotoxicity of mTHPC (Temoporfin) Loaded Polymeric Micelles Mediated by Lipase Catalyzed Degradation

Jan-Willem Hofman,Frits M Flesch,Myrra G Carstens,Femke Van Zeeland,Cornelus F Van Nostrum,Conny Helwig,Wim E Hennink

doi:10.1007/s11095-008-9590-7

Jan-Willem Hofman, Frits M Flesch + Show 5 more

Open Access

https://doi.org/10.1007/s11095-008-9590-7

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Abstract

PurposeTo study the in vitro photocytotoxicity and cellular uptake of biodegradable polymeric micelles loaded with the photosensitizer mTHPC, including the effect of lipase-catalyzed micelle degradation.MethodsMicelles of mPEG750-b-oligo(ɛ-caprolactone)5 (mPEG750-b-OCL5) with a hydroxyl (OH), benzoyl (Bz) or naphthoyl (Np) end group were formed and loaded with mTHPC by the film hydration method. The cellular uptake of the loaded micelles, and their photocytotoxicity on human neck squamous carcinoma cells in the absence and presence of lipase were compared with free and liposomal mTHPC (Fospeg®).ResultsMicelles composed of mPEG750-b-OCL5 with benzoyl and naphtoyl end groups had the highest loading capacity up to 30% (w/w), likely due to π–π interactions between the aromatic end group and the photosensitizer. MTHPC-loaded benzoylated micelles (0.5 mg/mL polymer) did not display photocytotoxicity or any mTHPC-uptake by the cells, in contrast to free and liposomal mTHPC. After dilution of the micelles below the critical aggregation concentration (CAC), or after micelle degradation by lipase, photocytotoxicity and cellular uptake of mTHPC were restored.ConclusionThe high loading capacity of the micelles, the high stability of mTHPC-loaded micelles above the CAC, and the lipase-induced release of the photosensitizer makes these micelles very promising carriers for photodynamic therapy in vivo.

Highlights

Photodynamic therapy (PDT) is an emerging method to treat superficial tumors, for example in the head/neck region, the digestive tract and the skin [1,2]
In this study we evaluated the suitability of biodegradable mPEG750-b-oligo(ɛ-caprolactone) based micelles for the formulation of mTHPC
It was shown that at mTHPC/polymer feed ratios up to 30% (w/w), the loading efficiency was almost quantitative (80–100%), resulting in loading capacities up to 30% and an mTHPC concentration in the dispersion of 3 mg/mL, which is markedly higher than the aqueous solubility of mTHPC (

Summary

Introduction

Photodynamic therapy (PDT) is an emerging method to treat superficial tumors, for example in the head/neck region, the digestive tract and the skin [1,2]. PDT uses a combination of a photosensitizer (PS) and laser light. Upon illumination of the photosensitizer in the presence of oxygen, reactive oxygen species (ROS) are formed. The anti-tumor effect of ROS is exerted either directly by killing tumor cells, or indirectly by damaging tumor-associated vasculature and inducing an immune response against the tumor cells [1,2,3]. PDT has many advantages compared to other cancer treatments, i.e. less invasive than surgery, and more targeted than chemotherapy as a result of selective illumination.

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