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

Abstract

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.