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

Abstract

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.

Advances of Photothermal Agents with Fluorescence Imaging/Enhancement Ability in the Field of Photothermal Therapy and Diagnosis

“…Palanikumar et al designed tumor-targeted upconversion nanospheres (Ce6-ALUMSNs) with multimodal imaging capabilities. 78 NaY-F 4 :Yb/Er/Gd and Bi 2 Se 3 were encapsulated in mesoporous silica shells and further loaded with photosensitizer Ce6 in silica spheres. NaYF 4 :Yb/Er converts NIR light into visible light, thereby stimulating Ce6 to produce cytotoxic ROS, and Bi 2 Se 3 effectively converts NIR light into heat.…”

“…In addition, as a representative of emerging light conversion materials, upconversion nanoparticles (UCNP) also have many applications in PTT combined therapy. Palanikumar et al designed tumor-targeted upconversion nanospheres (Ce6-ALUMSNs) with multimodal imaging capabilities . NaYF 4 :Yb/Er/Gd and Bi 2 Se 3 were encapsulated in mesoporous silica shells and further loaded with photosensitizer Ce6 in silica spheres.…”

Fabrication of folic acid-modified bovine serum albumin cloaked dual-drug loaded hollow mesoporous silica nanoparticles for pH-responsive and targeted delivery of gastric cancer therapy

“…Nanoparticle-based drug delivery vehicles that are triggered and targeted are seen as a suitable method to circumvent these constraints [ 11 ]. Mesoporous silica nanoparticles (MSNs) have garnered significant interest as drug carriers due to their distinct inherent characteristics, including adjustable shape, particle size, surface charges, pore size and volume, substantial specific surface area, and non-toxicity [ 12 ]. In addition, as compared to traditional MSNs, hollow MSNs (HMSNs) were discovered to have a significant drug-loading capacity because of their spacious hollow interior.…”

A pH-responsive nanoplatform with dual-modality imaging for enhanced cancer phototherapy and diagnosis of lung metastasis

“…Therefore, alongside improving the treatment of primary lesions, monitoring cancer metastasis is crucial [ 27 , 28 ]. In recent years, various NPs with diagnostic capabilities have emerged to detect metastatic cancers using techniques such as fluorescence imaging, magnetic resonance imaging (MRI), photoacoustic imaging and et al [ 29 – 31 ]. The combined application of multiple imaging modalities not only enhances diagnostic accuracy and cancer localization but also effectively tracks and monitors cancer progression in real time, contributing to the development of more personalized and effective treatment plans [ 32 – 34 ].…”