In vitro evaluation of innovative light-responsive nanoparticles for controlled drug release in intestinal PDT.

Nanoparticles (NP) have gained importance as drug delivery systems for pharmaceutical challenging drugs. Their size properties allow passive targeting of cancer tissue by exploiting the enhanced permeability and retention (EPR) effect. Furthermore, surface modifications enable an active drug targeting for diseased regions in the human body. Besides the advantages, the drug release from commonly used biodegradable NP is mostly depending on physiological circumstances. Hence, there is a need for a more controllable drug release. The use of light-responsive polymers is an innovative conception enabling a more distinct drug release by an external light stimulus. The idea provides potential for an increase in efficiency and safety of local therapies. In this study, innovative light-sensitive NP were investigated for a photodynamic therapy (PDT) of gastrointestinal tumors. Nanoparticles based on a newly developed light-responsive polycarbonate (LrPC) and poly(lactic-co-glycolic-acid) (PLGA) were loaded with the approved photosensitizer 5,10,15,20-tetrakis(m-hydroxyphenyl)chlorin (mTHPC). Mucus penetrating properties were obtained by surface PEGylation of the nanoparticles either by using LrPC in combination with a PEGylated PLA (PEG-PLA) or by a combination with PEGylated LrPC (LrPC-PEG). Cytotoxic potential in dependency of a light-induced drug release was investigated in different cytotoxicity assays. Intracellular accumulation in mucus producing colon-carcinoma cell line HT-29-MTX was analysed by HPLC and confocal laser microscopy.

The impact of gastrointestinal mucus on nanoparticle penetration - in vitro evaluation of mucus-penetrating nanoparticles for photodynamic therapy.

Over the last years nanoparticles (NP) have become a promising vehicle as drug delivery systems for photodynamic therapy (PDT), combining the advantages of an effective drug transport to the target cells and the reduction of undesired side effects. The in vitro evaluation of new nanoparticulate formulations has become a rising problem since cell culture models differ from the in vivo situation of the human body to a large extent. Particularly, in case of gastrointestinal tumors, after peroral application nanoparticles are challenged by overcoming the mucus layer as a first physical barrier before reaching the target cells, an aspect often neglected in literature. However, the presence of mucus is crucial for in vitro models to evaluate mucus-penetrating potential of surface-modified nanoparticulate drug carrier systems. Biodegradable poly(dl-lactide-co-glycolide) (PLGA) NP loaded with the model photosensitizer 5,10,15,20-tetrakis(m-hydroxyphenyl)porphyrin (mTHPP) were surface modified with either poly(ethylene glycol) (PEG) or chitosan (CS) to gain mucus-penetrating or mucoadhesive particle properties. All NP systems were compared to each other and to free mTHPP regarding cytotoxicity and cellular uptake in HT-29 cells and mucus producing HT-29-MTX cells. For PEGylated mTHPP-PLGA-PEG-NP a significantly higher accumulation was obtained in HT-29-MTX cells compared to all other tested nanoparticles and the free drug. Additionally, a mucus-containing Transwell® model, consisting of HT-29-MTX cells, confirmed these results, representing a promising in vitro screening method for mucus-penetrating particle properties.

Light-responsive nanoparticles based on new polycarbonate polymers as innovative drug delivery systems for photosensitizers in PDT.

Nanoparticles based on biodegradable polymers are well-known as approved carrier systems for a diversity of drugs. Despite their advantages, such as the option of an active drug targeting or the physicochemical protection of instable payloads, the controlled drug release often underlies intra- and interindividual influences and is therefore difficult to predict. To circumvent this limitation, the release behavior can be optimized using light-responsive materials for the nanoparticle preparation. The resulting light-responsive nanoparticles are able to release the embedded drug after an external light-stimulus, thereby increasing efficacy and safety of the therapy. In the present study light-responsive self-immolative polymers were used for the nanoparticle manufacturing. Light-responsive polycarbonates (LrPC) as well as PEGylated LrPC (LrPC-PEG) were synthesized via ring-opening polymerization of trimethylene carbonate-based monomers and fully physico-chemically characterized. Light-responsive nano formulations were obtained by blending LrPC or (LrPC-PEG) with the FDA-approved polymer poly(DL-lactide-co-glycolide) (PLGA). The nanoparticles were loaded with the photosensitizer 5,10,15,20-tetrakis(m-hydroxyphenyl)chlorin (mTHPC). The light-induced nanoparticle degradation was analyzed as well as the drug release behavior with and without illumination. Furthermore, biological safety of the degradation products was investigated in an in vitro cell culture study.

Mucus-penetrating nanoparticles: Promising drug delivery systems for the photodynamic therapy of intestinal cancer.

Photodynamic therapy (PDT) is an auspicious therapy approach for the treatment of cancer. Despite its numerous benefits, the drug delivery of the used photosensitizer (PS) to target locations inside the human body remains a main therapy challenge, since the standard intravenous PS injection often causes systemic side-effects. To circumvent this therapy drawback, the oral application represents a promising administration alternative. Especially for the treatment of intestinal cancer it offers the possibility of a local treatment with a reduced likelihood for adverse drug reactions. To establish a suitable drug delivery system for intestinal PDT, we developed nanoparticles (NP) of the biodegradable and biocompatible polymer poly(lactic-co-glycolic) acid (PLGA), loaded with the model PS 5,10,15,20-tetrakis(m-hydroxyphenyl)porphyrin (mTHPP). By functionalizing the particle surface with either poly(ethylene glycol) (PEG) or chitosan (CS), mucus-penetrating or mucoadhesive properties were obtained. These particle characteristics are important to enable an overcoming of the intestinal mucus barrier and thus lead to a PS accumulation close to and in the target cells. In permeation studies with a biosimilar mucus and in cell culture experiments with mucus-covered Caco-2 cells, PEG-modified NP were identified as a superior drug vehicle for an intestinal PDT, compared to surface unmodified or mucoadhesive NP.