Thermosensitive Nanogels with Cross-Linked Pd(II) Ions for Improving Therapeutic Effects on Platinum-Resistant Cancers via Intratumoral Formation of Hydrogels

Although bivalent palladium [Pd(II)] compounds exhibit favorable antitumor efficacy against platinum-resistant cancers, the mechanism remains unclear. Moreover, some drawbacks, such as structural lability, rapid elimination in vivo, and poor intratumoral retention, heavily limit their application in systemic tumor chemotherapy. Here, thermosensitive Pd-PNS nanogels are rationally designed by cross-linking coordination of Pd(II) ions with poly(styrenesulfonate-b-N-isopropylacrylamide-b-styrenesulfonate) (PNS), achieving high drug-loading ability (ca. 80% of entrapment efficiency and 40% of drug-loading efficiency), sustained release, and long-term retention of highly water-soluble K2PdCl4 in intratumoral administration. Cytotoxicity on sensitive/resistant MCF-7 cells and cancer stem cell (CSC) spheroids indicates that Pd-PNS nanogels could inhibit the palladium efflux of P-glycoprotein and multidrug resistance-associated protein-1 and thus enhance the DNA damage and toxicity of platinum-resistant MCF-7/Pt cells and their CSCs. Based on their temperature-sensitive sol–gel transition, Pd-PNS nanogels show sustained release profiles and long-term retention in tumors, further enhancing in vivo antitumor efficacy on MCF-7/Pt tumor-bearing BALB/c nude mice. Owing to these advantages of prolonged retention, efflux inhibition, and efficient CSCs killing ability, Pd-PNS nanogels are promising to be developed as a new temperature-sensitive delivery nanoplatform for injectable regional chemotherapy on platinum-resistant cancers.