Photoinduced effects of m-tetrahydroxyphenylchlorin loaded lipid nanoemulsions on multicellular tumor spheroids

Abstract

BackgroundPhotosensitizers are used in photodynamic therapy (PDT) to destruct tumor cells, however, their limited solubility and specificity hampers routine use, which may be overcome by encapsulation. Several promising novel nanoparticulate drug carriers including liposomes, polymeric nanoparticles, metallic nanoparticles and lipid nanocomposites have been developed. However, many of them contain components that would not meet safety standards of regulatory bodies and due to difficulties of the manufacturing processes, reproducibility and scale up procedures these drugs may eventually not reach the clinics. Recently, we have designed a novel lipid nanostructured carrier, namely Lipidots, consisting of nontoxic and FDA approved ingredients as promising vehicle for the approved photosensitizer m-tetrahydroxyphenylchlorin (mTHPC).ResultsIn this study we tested Lipidots of two different sizes (50 and 120 nm) and assessed their photodynamic potential in 3-dimensional multicellular cancer spheroids. Microscopically, the intracellular accumulation kinetics of mTHPC were retarded after encapsulation. However, after activation mTHPC entrapped into 50 nm particles destroyed cancer spheroids as efficiently as the free drug. Cell death and gene expression studies provide evidence that encapsulation may lead to different cell killing modes in PDT.ConclusionsSince ATP viability assays showed that the carriers were nontoxic and that encapsulation reduced dark toxicity of mTHPC we conclude that our 50 nm photosensitizer carriers may be beneficial for clinical PDT applications.Electronic supplementary materialThe online version of this article (doi:10.1186/s12951-016-0221-x) contains supplementary material, which is available to authorized users.

Drug delivery to solid tumors: the predictive value of the multicellular tumor spheroid model for nanomedicine screening

“…20 For example, 50 nm-sized lipid NPs showed a considerably deeper penetration and homogeneous distribution as compared to 120 nm-sized ones. 76 NPs .100 nm are too large to cross ECM interstitial spaces in spheroid 73,77 and are confined to the outer layers as demonstrated with gelatin NPs (210 nm) that only penetrated ~40 µm deep. 20 Micelles are generally smaller than liposomes and penetrate deeply and …”

Photodynamic therapy in 3D cancer models and the utilisation of nanodelivery systems

“…plates, hanging drop methods etc.) where they assume naturally a spherical aggregate conformation [67][68][69] or by embedding cells in a 3D matrix. The closely packed arrangement where cell to cell contact is dominant and the reduced rate of diffusion of drugs and oxygen through the spheroids makes them comparable to in vivo tissues.…”

Lipid nanoemulsions and liposomes improve photodynamic treatment efficacy and tolerance in CAL-33 tumor bearing nude mice

“…In a similar approach in our former studies we presented the successful encapsulation of mTHPC into fully biocompatible and biodegradable lipid nanoemulsions and showed first data in monolayer cells [ 23 , 24 ]. In our subsequent investigations in multicellular tumor spheroids we identified a formulation with a high mTHPC payload that featured the same excellent PDT effects as the free mTHPC but with a reduced dark toxicity (Lipidots) [ 25 ]. This nanoemulsion consists of a phospholipid (lecithin) monolayer, protected by a PEG-shell with a soybean/wax core, where mTHPC is incorporated.…”

“…We recently developed a biocompatible nanoemulsion (Lipidots) [ 23 ] as carrier for mTHPC with excellent optical properties which we subsequently tested in two in vitro studies [ 24 , 25 ]. It could be demonstrated that Lipidots can significantly lower the dark toxicity of mTHPC while maintaining its photodynamic activity.…”