A Three-Dimensional Printable Hydrogel Formulation for the Local Delivery of Therapeutic Nanoparticles to Cervical Cancer

Abstract

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.

Research progress and clinical application of stimuli-responsive hydrogels in cervical cancer

“…Another study found that the survival rate of Hela cells cultured with 30 mg-mL-1 SOLE/PEGDA decreased from 72.3% to 41.7% under NIR irradiation in poly(ethylene glycol) bisacrylate (PEGDA) composite hydrogels loaded with spinach extract (SOLE, a natural photosensitizer). It indicates that SOLE/PEGDA hydrogels are antitumor active in PDT treatment [57].…”

Gold-Nanoparticle Hybrid Nanostructures for Multimodal Cancer Therapy

“…As with liposomes, hydrogels can also be thermoresponsive and be used for specific heat-triggered drug release. Such thermoresponsive gels undergo a sol-to-gel transition when heated to a specific temperature (i.e., low critical gelation temperature), leading to drug release [ 153 , 154 ]. Several studies investigated thermo- and non-thermoresponsive GNP–hydrogel hybrids for cancer therapy.…”

“…Alginate-based thermosensitive hydrogels with GNPs were also studied for cancer therapy by Kiseleva et al, who used alginate combined with a thermosensitive polymer, PF127, to make thermoresponsive hydrogels for the encapsulation and release of GNPs. In this study, GNPs were used as the therapeutic agent to be released from the gel via gel dissolution and GNP diffusion without being triggered by heat [ 153 ]. Another alginate-based nanohybrid hosting both GNPs and iron oxide nanoparticles was studied for magnetically targeted drug delivery, PTT, and magnetic resonance imaging (MRI).…”

3D Printing of Self‐Assembling Nanofibrous Multidomain Peptide Hydrogels

“…Although multiple 3D printing methods exist, extrusion‐based printing has been most widely adopted due to its simplistic working principle and ease of use. [ 3,4 ] Inks used in extrusion 3D printing mainly consist of chemically modified versions of gelatin, [ 5–12 ] alginate, [ 13–16 ] hyaluronic acid, [ 17–20 ] collagen, [ 1,21,22 ] decellularized extracellular matrix, [ 23–25 ] or combinations of these. [ 26–35 ] The traditional approach for developing 3D printable inks has been to chemically modify naturally‐derived hydrogel materials to make them more printable, while attempting to maintain their favorable biological properties.…”

“…Although multiple 3D printing methods exist, extrusion-based printing has been most widely adopted due to its simplistic working principle and ease of use. [3,4] Inks used in extrusion 3D printing mainly consist of chemically modified versions of gelatin, [5][6][7][8][9][10][11][12] alginate, [13][14][15][16] hyaluronic acid, [17][18][19][20] collagen, [1,21,22] decellularized extracellular matrix, [23][24][25] or combinations of these. [26][27][28][29][30][31][32][33][34][35] The traditional approach for developing 3D printable inks invented a fabrication method that included extrusion printing followed by spraying a salt gelling agent at each layer.…”