Upper-Critical-Solution-Temperature Polymer Modified Gold Nanorods for Laser Controlled Drug Release and Enhanced Anti-Tumour Therapy


Abstract

Photothermal therapy (PTT) has become effective method for the treatment of malignant cancer. The development of PTT system with high anti-tumour effect is still the feasible research direction. Here, a new type of gold nanorods (AuNRs)-doxorubicin (DOX)/mPEG10K-peptide/P(AAm-co-AN) (APP-DOX) nano drug delivery system was proposed. Among them, AuNRs was used as high-efficiency photothermal agent. APP-DOX had a suitable size and can be targeted to accumulate in tumour tissues through circulation in the body. The abundant matrix metalloproteinase 2 (MMP-2) in the tumour environment intercepted and cut off the short peptide chain structure grafted on APP-DOX. At the same time, the removal of the PEG segment leaded to an increase in the hydrophobic properties of the system. Nanoparticles aggregated into large particles, causing them to stay and aggregate further at the tumour site. When irradiated by 808 nm near-infrared laser, APP-DOX achieved a gradual heating process. High temperature can effectively ablate tumours and enable UCST polymer to achieve phase transition, resulting in more anti-cancer drugs loaded in the polymer layer DOX was released, effectively killing cancer cells. Animal experiments had verified the possibility of the nano drug-carrying system and good tumour treatment effect. What''s more worth mentioning is that compared with free DOX, the nano drug delivery system had lower biological toxicity and not cause obvious harmful effects on normal organs and tissues.

Keywords: DOX; UCST polymer; drug delivery; gold nanorod; photothermal therapy; tumor treatment.

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

SCHEME 1
SCHEME 1
Illustration of the structure of APP-DOX and strategy of drug release at the tumour site.
FIGURE 1
FIGURE 1
1H-NMR spectra of P(AAm-co-AN)-DDAT (A). UV-Vis absorption spectra of AuNRs, LA-hyd-DOX, and APP-DOX (B). Light transmittance-temperature curve, particle size distribution, and photographs of the self-assembled vesicles of the P(AAm-co-AN)-DDAT (C). TEM images of AuNRs and APP-DOX (D). Light transmittance curve of the self-assembled vesicles of the P(AAm-co-AN)-DDAT copolymer under alternate cycles of 20 and 60°C (E). Photographs and micromechanism diagram of the AuNR-DOX turbidity change under 808?nm laser irradiation for 10?min (F). Curve of the change in the absorbance (optical density value) of AuNR-DOX during the heating process from 20 to 60°C (G). Particle size distribution curves of mPEG-AuNRs-DOX, APP-DOX, and APP-DOX co-incubated with MMP-2 before and after 808?nm laser irradiation (H).
FIGURE 2
FIGURE 2
Temperature change curves of APP-DOX solution and the same amount of PBS under laser irradiation (808?nm, 10?min) (A). Temperature change curves of APP-DOX solution under laser irradiation of different power densities (B). Temperature change curves of APP-DOX solution during the on/off switching cycles of laser irradiation (C). Temperature change curves of APP-DOX solution in a single on/off process of laser irradiation (D). Relationship between the cooling time and the negative natural logarithm of temperature driving force after the laser was turned off (E). Cumulative drug release curves (F) and the corresponding three-dimensional numerical histogram (G) of APP-DOX in pH 5.0 buffer at 37°C, at 50°C, and under the stimulation of NIR laser irradiation. Drug release curve of APP-DOX over 300?min of on/off cycles of NIR laser irradiation (H).
FIGURE 3
FIGURE 3
Fluorescence microscopic images of HepG2 cells incubated with free DOX, mPEG-AuNRs-DOX, and APP-DOX for 4?h (scale bar represents 10?μm).
FIGURE 4
FIGURE 4
Numerical histogram (A,B) and broken-line graph (C) of HepG2 cells viability after treatment with nanomaterials under laser irradiation and the histogram of the relationship between laser irradiation time and cell survival rate (D).
FIGURE 5
FIGURE 5
The efficacy of PBS, DOX, mPEG-AuNRs-DOX, and APP-DOX in treatment of subcutaneous hepatocellular carcinoma xenograft tumours in nude mice. Images of the tumours in nude mice (A). Bar graph of tumour weight in each group of nude mice (B). Weight change curves of the various groups of nude mice (C). Curves of the relative tumour volume change (D). Photographs of nude mice and H&E staining images of the pathological sections of tumours and main organs (heart, liver, spleen, lung, and kidney) (E).
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