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Cervical cancer is the fourth most common malignancy among women. Compared to other types of cancer, therapeutic agents can be administrated locally at the mucosal vaginal membrane. Thermosensitive gels have been developed over the years for contraception or for the treatment of bacterial, fungal, and sexually transmitted infections. These formulations often carry therapeutic nanoparticles and are now being considered in the arsenal of tools for oncology. They can also be three-dimensionally (3D) printed for a better geometrical adjustment to the anatomy of the patient, thus enhancing the local delivery treatment. In this study, a localized delivery system composed of a Pluronic F127-alginate hydrogel with efficient nanoparticle (NP) release properties was prepared for intravaginal application procedures. The kinetics of hydrogel degradation and its NP releasing properties were demonstrated with ultrasmall gold nanoparticles (∼80% of encapsulated AuNPs released in 48 h). The mucoadhesive properties of the hydrogel formulation were assayed by the periodic acid/Schiff reagent staining, which revealed that 19% of mucins were adsorbed on the gel's surface. The hydrogel formulation was tested for cytocompatibility in three cell lines (HeLa, CRL 2616, and BT-474; no sign of cytotoxicity revealed). The release of AuNPs from the hydrogel and their accumulation in vaginal membranes were quantitatively measured in vitro / ex vivo with positron emission tomography, a highly sensitive modality allowing real-time imaging of nanoparticle diffusion (lag time to start of permeation of 3.3 h, 47% of AuNPs accumulated in the mucosa after 42 h). Finally, the potential of the AuNP-containing Pluronic F127-alginate hydrogel for 3D printing was demonstrated, and the geometrical precision of the 3D printed systems was measured by magnetic resonance imaging (<0.5 mm precision; deviation from the design values <2.5%). In summary, this study demonstrates the potential of Pluronic F127-alginate formulations for the topical administration of NP-releasing gels applied to vaginal wall therapy. This technology could open new possibilities for photothermal and radiosensitizing oncology applications.

Ultrasmall nanoparticles (US-NPs; <20 nm in hydrodynamic size) are now included in a variety of pharmacological and cosmetic products, and new technologies are needed to detect at high sensitivity the passage of small doses of these products across biological barriers such as the skin. In this work, a diffusion cell adapted to positron emission tomography (PET), a highly sensitive imaging technology, was developed to measure the passage of gold NPs (AuNPs) in skin samples in continuous mode. US-AuNPs (3.2 nm diam.; TEM) were functionalized with deferoxamine (DFO) and radiolabeled with 89 Zr (IV) (half-life: 3.3 days, matching the timeline of diffusion tests). The physicochemical properties of the functionalized US-AuNPs (US-AuNPs-PEG-DFO) were characterized by FTIR (DFO grafting; hydroxamate peaks: 1629.0 cm -1 , 1569.0 cm -1 ), XPS (presence of the O═C-N C 1s peak of DFO at 287.49 eV), and TGA (organic mass fraction). The passage of US-AuNPs-PEG-DFO- 89 Zr (IV) in skin samples was measured by PET, and the diffusion parameters were extracted thereby. The signals of radioactive US-AuNPs-PEG-DFO- 89 Zr (IV) leaving the donor compartment, passing through the skin, and entering the acceptor compartment were detected in continuous at concentrations as low as 2.2 nM of Au. The high-sensitivity acquisitions performed in continuous allowed for the first time to extract the lag time to the start of permeation, the lag time to start of the steady state, the diffusion coefficients, and the influx data for AuNPs permeating into the skin. PET could represent a highly valuable tool for the development of nanoparticle-containing topical formulations of drugs and cosmetics.