Title : Cyclodextrin-based photoactive liposomal nanoparticles for tumor targeting
Application of meta-tetra(hydroxyphenyl)chorin (mTHPC), one of the most potent photosensitizer (PS), in the photodynamic therapy (PDT) of solid tumors encounters several complications resulting from its insolubility in aqueous medium. It requires low light doses and concentrations to be photoactive (Senge & Brandt, 2011), however mTHPC aggregation results in reduced photodynamic activity, moderate selectivity and skin photosensitivity (Kachatkou et al., 2009). To improve the transport of mTHPC to target tissue and to strengthen its intra-tissue accumulation, several nanoconstructions have been investigated such as liposomes, polymeric nanoparticles, inclusion complexes etc.
In the present study, we suggested the coupling of two independent delivery systems by encapsulating Cyclodextrin/mTHPC inclusion complexes into liposomes to achieve drug-in-cyclodextrin-in-liposome (DCL) nanoparticles. DCL could circumvent the drawbacks of each separate system. Liposomes offer an excellent opportunity to achieve selective drug targeting which is expected to optimize the pharmacokinetic parameters, prevent local irritation, and reduce drug toxicity. In its turn, cyclodextrins (CDs) are cyclic oligosaccharides, which have been utilized as independent carriers for improvement of pharmaceutical properties such as solubility, stability and bioavailability of various drug molecules, including mTHPC (Yankovsky et al., 2016, Yakavets et al., 2017). Therefore, encapsulation of CD-complexed drug into liposomes may increase the drug loading capacity, entrapment efficiency, restrain the dissociation of drug-CD complexes and prolong its systemic circulation. The aim of this study was to evaluate the effect of DCLs on mTHPC behavior at various stages of its distribution in tumor models in vitro.
For this purpose, we have prepared DCL with various compositions to optimize DCL structures in terms of mTHPC delivery. We have studied the influence of DCLs on mTHPC accumulation, distribution and photodynamic efficiency in human adenocarcinoma HT29 cellular monolayer and spheroid models. We have demonstrated that mTHPC-DCLs are stable and almost all PS is bound to β-CDs in the inner aqueous liposome core. We studied mTHPC accumulation and localization in both HT29 monolayer and spheroid cells. Cellular uptake and intracellular localization of mTHPC-based DCL was similar to liposomal mTHPC in monolayer cultures. However, in HT29 3D multicellular tumor spheroids the application of DCLs significantly improved PS compared to other formulations resulting in homogeneous distribution of mTHPC across spheroids.
The data obtained confirm the interest of hybrid nanostructures in mTHPC-PDT.
Acknowledgements: This study was supported by Belarussian Republican Foundation for Fundamental Research, the Ministry of Education of the Republic of Belarus and French “Ligue National contre le Cancer”. The authors thank biolitec research GmbH (Jena, Germany) for providing mTHPC.
Audience take away:
• This presentation establishes the action of cyclodextrins as nanoshuttles for aryl porphyrin molecules used as photosensitizers. This is the new action mechanism of cyclodextrins application in pharmaceutics.
• The combined action of liposomes and cyclodextrins as nanocarriers could provide the new strategy in nanoparticles design.
• Our study offers a smart selection of essential parameters for nanoparticles screening based on several tumor models and analysis techniques.