pH-Responsive Upconversion Mesoporous Silica Nanospheres for Combined Multimodal Diagnostic Imaging and Targeted Photodynamic and Photothermal Cancer Therapy.

Photodynamic therapy (PDT) and photothermal therapy (PTT) have gained considerable attention as potential alternatives to conventional cancer treatments. However, these approaches remain limited by low solubility, poor stability, and inefficient targeting of many common photosensitizers (PSs) and photothermal agents (PTAs). To overcome the aforementioned limitations, we engineered biocompatible and biodegradable tumor-targeted upconversion nanospheres with imaging capabilities. The multifunctional nanospheres consist of a sodium yttrium fluoride core doped with lanthanides (ytterbium, erbium, and gadolinium) and the PTA bismuth selenide (NaYF4:Yb/Er/Gd,Bi2Se3) enveloped in a mesoporous silica shell that encapsulates a PS, chlorin e6 (Ce6), within its pores. NaYF4:Yb/Er converts deeply penetrating near-infrared (NIR) light to visible light, which excites Ce6 to generate cytotoxic reactive oxygen species (ROS), while Bi2Se3 efficiently converts absorbed NIR light to heat. Additionally, Gd enables magnetic resonance imaging of the nanospheres. The mesoporous silica shell is coated with DPPC/cholesterol/DSPE-PEG to retain the encapsulated Ce6 and prevent serum protein adsorption and macrophage recognition that hinder tumor targeting. Finally, the coat is conjugated to the acidity-triggered rational membrane (ATRAM) peptide, which promotes specific and efficient internalization into malignant cells in the mildly acidic microenvironment of tumors. The nanospheres facilitated tumor magnetic resonance and thermal and fluorescence imaging and exhibited potent NIR laser light-induced anticancer effects in vitro and in vivo via combined ROS production and localized hyperthermia, with negligible toxicity to healthy tissue, hence markedly extending survival. Our results demonstrate that the ATRAM-functionalized, lipid/PEG-coated upconversion mesoporous silica nanospheres (ALUMSNs) offer multimodal diagnostic imaging and targeted combinatorial cancer therapy.

pH-responsive upconversion mesoporous silica nanospheres for combined multimodal diagnostic imaging and targeted photodynamic and photothermal cancer therapy.

Photodynamic therapy (PDT) and photothermal therapy (PTT) have garnered considerable interest as non-invasive cancer treatment modalities. However, these approaches remain limited by low solubility, poor stability and inefficient targeting of many common photosensitizers (PSs) and photothermal agents (PTAs). To overcome these limitations, we have designed biocompatible and biodegradable tumor-targeted upconversion nanospheres with imaging capabilities. The multifunctional nanospheres consist of a sodium yttrium fluoride core doped with lanthanides (ytterbium, erbium and gadolinium) and bismuth selenide (NaYF 4 :Yb/Er/Gd,Bi 2 Se 3 ) within a mesoporous silica shell that encapsulates a PS, Chlorin e6 (Ce6), in its pores. NaYF 4 :Yb/Er converts deeply penetrating near-infrared (NIR) light to visible light, which excites the Ce6 to generate cytotoxic reactive oxygen species (ROS), while the PTA Bi 2 Se 3 efficiently converts absorbed NIR light to heat. Additionally, Gd enables magnetic resonance imaging (MRI) of the nanospheres. The mesoporous silica shell is coated with lipid/polyethylene glycol (DPPC/cholesterol/DSPE-PEG) to ensure retention of the encapsulated Ce6 and minimize interactions with serum proteins and macrophages that impede tumor targeting. Finally, the coat is functionalized with the acidity-triggered rational membrane (ATRAM) peptide, which promotes specific and efficient internalization into cancer cells within the mildly acidic tumor microenvironment. Following uptake by cancer cells in vitro , NIR laser irradiation of the nanospheres caused substantial cytotoxicity due to ROS production and hyperthermia. The nanospheres facilitated tumor MRI and thermal imaging, and exhibited potent NIR laser light-induced antitumor effects in vivo via combined PDT and PTT, with no observable toxicity to healthy tissue, thereby substantially prolonging survival. Our results demonstrate that the ATRAM-functionalized, lipid/PEG-coated upconversion mesoporous silica nanospheres (ALUMSNs) offer multimodal diagnostic imaging and targeted combinatorial cancer therapy.

Protein mimetic amyloid inhibitor potently abrogates cancer-associated mutant p53 aggregation and restores tumor suppressor function.

Missense mutations in p53 are severely deleterious and occur in over 50% of all human cancers. The majority of these mutations are located in the inherently unstable DNA-binding domain (DBD), many of which destabilize the domain further and expose its aggregation-prone hydrophobic core, prompting self-assembly of mutant p53 into inactive cytosolic amyloid-like aggregates. Screening an oligopyridylamide library, previously shown to inhibit amyloid formation associated with Alzheimer's disease and type II diabetes, identified a tripyridylamide, ADH-6, that abrogates self-assembly of the aggregation-nucleating subdomain of mutant p53 DBD. Moreover, ADH-6 targets and dissociates mutant p53 aggregates in human cancer cells, which restores p53's transcriptional activity, leading to cell cycle arrest and apoptosis. Notably, ADH-6 treatment effectively shrinks xenografts harboring mutant p53, while exhibiting no toxicity to healthy tissue, thereby substantially prolonging survival. This study demonstrates the successful application of a bona fide small-molecule amyloid inhibitor as a potent anticancer agent.