Mitochondria-targeting polydopamine-coated nanodrugs for effective photothermal- and chemo-synergistic therapies against lung cancer

Abstract

Targeting mitochondria via nano platform emerged as an attractive anti-tumor pathway due to the central regulation role in cellar apoptosis and drug resistance. Here, a mitochondria-targeting nanoparticle (TOS-PDA-PEG-TPP) was designed to precisely deliver polydopamine (PDA) as the photothermal agent and alpha-tocopherol succinate (α-TOS) as the chemotherapeutic drug to the mitochondria of the tumor cells, which inhibits the tumor growth through chemo- and photothermal- synergistic therapies. TOS-PDA-PEG-TPP was constructed by coating PDA on the surface of TOS NPs self-assembled by α-TOS, followed by grafting PEG and triphenylphosphonium (TPP) on their surface to prolong the blood circulation time and target delivery of TOS and PDA to the mitochondria of tumor cells. In vitro studies showed that TOS-PDA-PEG-TPP could be efficiently internalized by tumor cells and accumulated at mitochondria, resulting in cellular apoptosis and synergistic inhibition of tumor cell proliferation. In vivo studies demonstrated that TOS-PDA-PEG-TPP could be efficiently localized at tumor sites and significantly restrain the tumor growth under NIR irradiation without apparent toxicity or deleterious effects. Conclusively, the combination strategy adopted for functional nanodrugs construction aimed at target-delivering therapeutic agents with different action mechanisms to the same intracellular organelles can be extended to other nanodrugs-dependent therapeutic systems.

Keywords: alpha-tocopherol succinate (α-TOS); chemo- and photothermal- synergistic therapies; lung cancer; mitochondria-targeting.

Graphical abstract

Figure 1.

(A) The synthesis routes of mitochondria-targeting TOS-PDA-PEG-TPP NPs. (B) The size, (C) Zeta potential and (D) FTIR spectra of nanoparticles. (E) The morphologies of (e1) TOS NPs, (e2) TOS-PDA-PEG NPs, and (e3) TOS-PDA-PEG-TPP NPs.

Figure 2.

(A) Temperature changes of four groups of different materials after NIR irradiation. (B) Light stability of TOS-PDA-PEG-TPP for four consecutive exposures in 80 min.

Figure 3.

(A) Flow cytometry analysis of cellular uptake of indicated nanoparticles. (B) Confocal laser images of the intake of nanoparticles by LLC cells (4 h). (C) Schematic diagram of mitochondrial membrane potential damage caused by nanoparticles entering mitochondria. (D) Quantitative analysis (CLSM) of indicated nanoparticles entering mitochondria after 4 h co-culture with LLC cells.

Figure 4.

(A) Laser confocal images of indicated groups after JC-1 staining of 6 h co-culture (scale bar =50μm). (B) Semi-quantitative analysis of fluorescence intensity of JC-1 staining. (C) The confocal image of tunel after 24 h co-culture with indicated nanoparticles (scale bar = 50μm). (D) Semi-quantitative analysis of fluorescence intensity of tunel. (E) Flow cytometric analysis of annexin V and 7-AAD double staining after 24 h co-culture of indicated groups. (F) Protein levels of Parp1, Bax and Caspase 3 of indicated groups.

Figure 5.

(A) Distribution of drugs in mice at different time points (2 h, 4 h, 12 h, 24 h, 36 h) after tail vein injection. (B) The temperature changes of mice after different drugs were injected into the tail vein and irradiated by NIR. (C) Temperature changes at the tumor site over 10 min.

Figure 6.

(A) Schematic diagram of tumor inoculation and administration in mice. (B) Body weight changes of mice in indicated groups after drug injection. (C) Tumor images of indicated groups of mice after treatment. (D) Changes in tumor volume in six groups during treatment. (E) Statistical map of tumor weight of six groups of mice after treatment.

Figure 7.

(A) HE staining (lung, liver, spleen, kidney, heart and tumor) of mice treated with indicated drugs (scale bar = 100 μm). (B) Immunohistochemical staining (Ki-67, CD31) of indicated mice treated with different drugs (scale bar =100 μm).