Multifunctional hybrid silica nanoparticles for controlled doxorubicin loading and release with thermal and pH dually response

Abstract

Controlled drug loading and release into tumor cells to increase the intracellular drug concentration is a major challenge for cancer therapy due to resistance and inefficient cellular uptake. Here a temperature and pH dually responsive PNiPAM/AA@SiO₂ core-shell particles with internal controlled release were designed and fabricated for efficient cancer treatment, which could recognize the intrinsic pH differences between cancers and normal tissues. Upon lowering the temperature, doxorubicin was loaded into the PNiPAM/AA@SiO₂ nanoparticles, whereas by increasing the acidity, previously loaded doxorubicin was quickly released. Comparing with common mesoporous silica particles (MSNs), this core-shell particle has more uniform size and better dispersity. In addition, dried PNiPAM/AA@SiO₂ nanoparticles could be easily redispersed in distilled water. The in vitro cell culture experiments showed that not only PNiPAM/AA@SiO₂ particles were more biocompatible and lower cytotoxic than MSN, but also DOX@PNiPAM/AA@SiO₂ had higher drug releasing efficiency in the lysosomes and stronger inhibitory effect on tumor cell growth than DOX@MSN. All these features indicated that PNiPAM/AA@SiO₂ particles have great potential in therapy applications.

Fig. 1

TEM images of mesoporous SiO₂ (a), PNiPAM/AA nanoparticles (b) and PNiPAM/AA@SiO₂ nanoparticles (c).

Fig. 2

FT-IR spectra of MSN, PNiPAM/AA and PNiPAM/AA@SiO₂ nanoparticles.

Fig. 3

(a) The photograph of colloidal solution of PNiPAM/AA@SiO₂ particles before and after drying; (b) Change of size and polydispersity of PNiPAM/AA@SiO₂ and MSN in water before and after drying.

Fig. 4

(a) hydrodynamic diameter distributions; (b) colloidal solutions of FITC-PNiPAM/AA@SiO₂ particles; (c) a photograph of aqueous solution of FITC-PNiPAM/AA@SiO₂ particles under illumination.

Fig. 5

The effect of temperature changing on hydrodynamic diameter of PNiPAM/AA@SiO₂ nanoparticles.

Fig. 6

The schematic diagram for the mechanism of drug loading of DOX@PNiPAM/AA@SiO₂ nanoparticles.

Fig. 7

DOX release profiles from DOX@MSN, DOX@PNiPAM/AA@SiO₂ (a) and PNiPAM/AA nanoparticles (b) under different pH.

Fig. 8

The cytotoxicity and cellular uptake of different nanoparticles to MCF-7 cells. (a) Viability of cells cultured in vitro with DOX loaded PNiPAM@SiO₂, MSN and blank carriers; (b) Flow cytometric analyses of DOX@PNiPAM/AA@SiO₂ (red line) and DOX@MSN (green line) at different time.

Fig. 9

Intracellular location of free DOX, DOX@ PNiPAM/AA@SiO₂ and DOX@MSN. MCF-7 cells incubated with DOX@ PNiPAM/AA@SiO₂ after 1 h (a) and 4 h (b) and MCF-7 cells incubated with DOX@MSN after 1 h (c) and 4 h (d).