title: Redox-sensitive cross-linking enhances albumin nanoparticle function as delivery system for photodynamic cancer therapy.
abstract: Photodynamic cancer therapy is still limited in its efficiency because of a lack of targeted methods avoiding non-specific toxicity. To overcome this we developed a system that is solely effective upon cellular uptake and intracellular activation by incorporating redox-sensitive chemistry. We used a nanoprecipitation method to obtain human serum albumin nanoparticles (HSA NP) with a diameter of 295 ± 5 nm and decorated them with the photosensitizer (PS) chlorin e6 (Ce6). The NP were stabilized using a redox-sensitive cross-linker to create a smart drug delivery system that is activated only upon NP disintegration in the reducing intracellular environment. Indeed, our drug delivery NP broke down in an environment emulating the reducing intracellular environment with 10 mM glutathione, but not under extracellular conditions. In contrast, the control cross-linked with glutaraldehyde did not break down in the reducing environment. Upon NP disintegration Ce6 fluorescence doubled as the result of diminished self-quenching. While the Ce6-HSA NP did not produce a significant amount of singlet oxygen upon irradiation, NP disintegration restored singlet oxygen production to about half of the value generated by the free Ce6. In vitro experiments with HeLa cells showed that the smart system was able to kill up to 81% of the cells while the glutaraldehyde cross-linked control only killed 56% of them at a drug concentration of 10 ng/ml. Also, Ce6 immobilization in HSA NP prevented dark toxicity in three different cell lines. For the first time, we demonstrate that it is possible to design a smart NP drug delivery system delivering a PS drug to cancer cells while avoiding toxicity prior to the uptake and irradiation. This finding may provide a means of designing more efficient PDT in cancer treatment.
authors.affiliation: Department of Chemistry, University of Puerto Rico, Río Piedras Campus, San Juan, PR 00931, USA.
authors.forename: Anna M
authors.initials: AM
authors.lastname: Molina
authors.affiliation: Department of Biology, University of Puerto Rico, Río Piedras Campus, San Juan, PR 00931, USA.
authors.forename: Moraima
authors.initials: M
authors.lastname: Morales-Cruz
authors.affiliation: Department of Biology, University of Puerto Rico, Río Piedras Campus, San Juan, PR 00931, USA.
authors.forename: Marimar
authors.initials: M
authors.lastname: Benítez
authors.affiliation: Department of Chemistry, University of Puerto Rico, Río Piedras Campus, San Juan, PR 00931, USA.
authors.forename: Kiara
authors.initials: K
authors.lastname: Berríos
authors.affiliation: Department of Chemistry, University of Puerto Rico, Río Piedras Campus, San Juan, PR 00931, USA.
authors.forename: Cindy M
authors.initials: CM
authors.lastname: Figueroa
authors.affiliation: Department of Biology, University of Puerto Rico, Río Piedras Campus, San Juan, PR 00931, USA.
authors.forename: Kai
authors.initials: K
authors.lastname: Griebenow
keywords: albumin nanoparticles; drug delivery system; photodynamic therapy; redox-responsive