A Multifunctional Nanocrystalline CaF2:Tm,Yb@mSiO2 System for Dual-Triggered and Optically Monitored Doxorubicin Delivery

Abstract

Daunting challenges in investigating the controlled release of drugs in complicated intracellular microenvironments demand the development of stimuli-responsive drug delivery systems. Here, a nanoparticle system, CaF₂:Tm,Yb@mSiO₂, made of a mesoporous silica (mSiO₂) nanosphere with CaF₂:Tm,Yb upconversion nanoparticles (UCNPs) is developed, filling its mesopores and with its surface-modified with polyacrylic acid for binding the anticancer drug molecules (doxorubicin, DOX). The unique design of CaF₂:Tm,Yb@mSiO₂ enables us to trigger the drug release by two mechanisms. One is the pH-triggered mechanism, where drug molecules are preferentially released from the nanoparticles at acidic conditions unique for the intracellular environment of cancer cells compared to normal cells. Another is the 808 nm near infrared (NIR)-triggered mechanism, where 808 nm NIR induces the heating of the nanoparticles to weaken the electrostatic interaction between drug molecules and nanoparticles. In addition, luminescence resonance energy transfer occurs from the UCNPs (the energy donor) to the DOX drug (the energy acceptor) in the presence of 980 nm NIR irradiation, allowing us to monitor the drug release by detecting the vanishing blue emission from the UCNPs. This study demonstrates a new multifunctional nanosystem for dual-triggered and optically monitored drug delivery, which will facilitate the rational design of personalized cancer therapy.

Figure 1

a) SEM image (the inset shows the UCNP dispersions in aqueous solution and particle size distribution), b) TEM images, c) X-ray diffraction patterns, and d) Photoluminescence spectrum of crystalline CaF₂:Tm,Yb@mSiO₂ nanospheres (the inset shows the optical image of nanospheres under excitation by 980 nm laser and the scale bar is 1 mm).

Figure 2

a) FTIR spectra of the CaF₂:Tm,Yb@mSiO₂ nanospheres before and after PAA modification; b) Zeta potential of UCNPs with or without PAA modification; c) relative cell viability of HEK293 cells incubated with PAA functionalized nanospheres of varied concentrations for 24 and 48 h.

Figure 3

a) DOX loading efficiency of UCNPs before and after PAA modification, b) FTIR spectra and enlarged characteristic peaks of PAA modified UCNPs before and after DOX loading.

Figure 4

a) The emission spectrum of PAA-modified UCNPs and the UV–vis absorption spectrum of DOX; b) The UC PL emission spectra of PAA modified nanoparticles before and after DOX loading under the excitation by 980 nm laser (the insets show the optical images captured by digital camera).

Figure 5

a) Cumulative DOX release profiles of nanoparticles in the medium with different pH values. The change of upconversion emission spectra of nanoparticles as a function of drug release time in the medium with pH of b) 7.4 and c) 4.7; d) the relationship between the intensity ratio of blue and red emission spectra (I_blue/I_red) and the DOX release time in medium with a different pH value.

Figure 6

a) DOX release profile of PAA modified nanoparticles in the neutral PBS solution (pH = 7.4) with and without NIR laser irradiation. b) Relative cell viability (to blank control) of free DOX and DOX loaded PAA modified nanoparticles with or without the NIR irradiation (λ = 808 nm, 1 W cm⁻², 10 min). c) Cell viability of MCF-7 cells exposed to different time (0–20 min) of laser irradiation (NIR 808 nm, 1 W cm⁻²) at DOX concentration of 0.01 µg mL⁻¹. d) LSCM images of MCF-7 cell incubated with DOX loaded PAA modified nanoparticles at different concentration (0–0.1 µg mL⁻¹) for 24 h and then irradiation with NIR. For each panel, images from left to right show the MCF-7 cell nuclei stained by DAPI (blue), DOX fluorescence in cells (red), and overlay of both images (Scale bar: 20 µm).

Scheme 1

Schematic illustration of CaF₂:Tm,Yb@mSiO₂ nanospheres for DOX delivery.