Separable double-layered microneedle-based transdermal codelivery of DOX and LPS for synergistic immunochemotherapy of a subcutaneous glioma tumor

Abstract

An efficient and patient-friendly process for administering immunochemotherapy is achieved through microneedle (MN)-mediated drug delivery into the dermal interstitium across the stratum corneum. Herein, we designed an interpenetrating polymer network (IPN) hydrogel to fabricate separable MNs for transdermal codelivery of lipopolysaccharide (LPS) and doxorubicin (DOX) for a synergistic immunochemotherapeutic outcome. The MN arrays were fabricated from IPN hydrogel which was prepared via sequential photoionic crosslinking of sodium alginate and sulfobetaine methacrylate using N, N’-methylenebisacrylamide and Ca2+ ion for chemical and ionic crosslinking, respectively. Tensile and compression tests revealed that the mechanical strength of the IPN hydrogel increased significantly and the MN array enabled skin penetration. The separable backbone of the MNs was prepared using a disulfide-crosslinked IPN hydrogel that was easily removed by disulfide bond cleavage with 1,4-dithiothreitol and ethylenediaminetetraacetic acid solution, whereas the dual drug-loaded MN patch was left in the skin to allow steady drug release. In vitro drug release tests demonstrated that the MN array allowed the timely release of drugs due to the hydrogel's rapid degradation. The IC50 value of DOX@MNs (1.088 µg/ml) against the CT-2A-Luc cell line indicated that the drug loaded onto the MNs was more than sufficient to kill cancer cells. Moreover, in vivo tumor suppression experiment on glioma-bearing C57BL/6 mice confirmed that the dual drug-loaded MNs (LPS/DOX@MNs) led to excellent upregulation of immune response and tumor inhibition, signifying its synergistic immunochemotherapeutic effects. Thus, the concept of MN-mediated combined immunochemotherapy provides localized sustained delivery and is a promising new treatment method for obtaining efficient synergistic therapeutic values.