GSH-pH dual-responsive engineered codoped Prussian blue multimodal theranostic nanoplatform induces TP53 deregulated apoptotic death of MDA-MB-231 with enhanced T₁ - T₂W MRI

Though chemotherapy is an effective clinical treatment, individual drugs hardly achieve precise controlled release, causing unavoidable severe side effects due to off-targeting in the absence of any receptor of triple negative breast cancer (TNBC). Fortunately, the emergence of on-demand drug-release nanoparticles allows potential alternatives to overcome the limitation. In this work, a dual-responsive multimodal theranostic targeted smart nanoplatform has been prepared by employing mesoporous silica (mSiO2)-coated Dy3+, Gd3+-codoped Prussian blue nanocubes (PBNCs) with CytC as a gatekeeper to seal pores of mSiO2 via disulfide and boronate ester bonds as intermediate linkers for intracellular high glutathione, and acidic pH responsive drug release. Hyaluronic acid has been used as a targeting motif, facilitating the uptake of our synthesized nanoplatform, wherein a cumulative drug-release profile demonstrated that the nanoplatform exhibits very low sustained drug release at pH 7.0 (∼20% in 25 h), while the release gets accelerated at pH 5.0 and 8.0 mM GSH (∼60% in 25 h), realizing the “trigger release” of drug. The nanoplatform possesses excellent biocompatibility to HEK 293 cells, while it has high cytotoxicity (∼67%) toward TNBC (IC50 = 35.8 μM), ascribed to synergistic chemo-phototherapeutic effect. An in silico analysis, followed by immunocytochemical studies illustrate that the down-regulated TP53-BAX/BCL2 and upregulated CASP3 CYTS networks initiate an apoptotic cell-death mechanism. In addition, the nanoplatform exhibits potency as a dual-mode MRI contrast agent with high relaxivity (r1 and r2) values of ∼7.84 and ∼29.3 mM–1 s–1, which will be highly facilitating for the diagnosis and tracking of TNBC management for personalized medicine.