A Versatile PDA(DOX) Nanoplatform for Chemo-Photothermal Synergistic Therapy against Breast Cancer and Attenuated Doxorubicin-Induced Cardiotoxicity

Abstract

Photothermal therapy (PTT) is a highly clinical application promising cancer treatment strategy with safe, convenient surgical procedures and excellent therapeutic efficacy on superficial tumors. However, a single PTT is difficult to eliminate tumor cells completely, and tumor recurrence and metastasis are prone to occur in the later stage. Chemo-photothermal synergistic therapy can conquer the shortcomings by further killing residual tumor cells after PTT through systemic chemotherapy. Nevertheless, chemotherapy drugs' extreme toxicity is also a problematic issue to be solved, such as anthracycline-induced cardiotoxicity. Herein, we selected polydopamine nanoparticles (PDA) as the carrier of the chemotherapeutic drug doxorubicin (DOX) to construct a versatile PDA(DOX) nanoplatform for chemo-photothermal synergistic therapy against breast cancer and simultaneously attenuated DOX-induced cardiotoxicity (DIC). The excellent photothermal properties of PDA were used to achieve the thermal ablation of tumors. DOX carried out chemotherapy to kill residual and occult distant tumors. Furthermore, the PDA(DOX) nanoparticles significantly alleviate DIC, which benefits from PDA's excellent antioxidant enzyme activity. The experimental data of the chemotherapy groups showed that the results of the PDA(DOX) group were much better than the DOX group. This study not only effectively inhibits cancer but tactfully attenuates DIC, bringing a new perspective into synergistic therapy against breast cancer.

Keywords: Doxorubicin-induced cardiotoxicity; Oxidative stress; Photothermal-chemotherapy synergistic therapy; Polydopamine.

Scheme 1

Schematic illustration of PDA(DOX) nanoplatform for chemo-photothermal synergistic therapy against breast cancer and attenuated doxorubicin-induced cardiotoxicity

Fig. 1

Synthesis and characterization of PDA-i and PDA(DOX) nanoparticles. a–d TEM images and size distributions of PDA-i; e Relationship between mean particle size and ammonium hydroxide content; f, g DLS and zeta potential of PDA-i and PDA(DOX); h The DOX loading efficiency and capacity of PDA(DOX) nanoparticles obtained under different PDA/DOX mass ratio reaction conditions; i Fluorescence spectrum of PDA-i and PDA(DOX) of various DOX loading capacity; j Release kinetics curves of PDA(DOX) under different pH or temperature

Fig. 2

Photothermal and antioxidation performance of PDA-i and PDA(DOX) nanoparticles. a Thermal images recorded for PDA-i and PDA(DOX); b Photothermal temperature rise curves (100 μg/mL); c Temperature rise and fall curves (50 μg/mL); d Photothermal conversion efficiencies and Molar extinction coefficients; e Photothermal repeatability curves under five on/off cycles (50 μg/mL); f Inhibitor rate of SOD; g Antioxidant Capacity of PDA-i and PDA(DOX)

Fig. 3

Cytotoxicity and in vitro curative effects. a–c The cytotoxicity of various concentrations of PDA(DOX) and DOX on MCF-10A cells, H9C2 cells, and 4T1 cells; d The cytotoxicity of various concentrations of PDA and PDA(DOX) on 4T1 cells; e The photothermal killing effects of PDA or PDA(DOX) on 4T1 cells after NIR irradiation at a laser power of 1.5 W for 5 min; f The synergetic effect of photothermal therapy and chemotherapy on 4T1 cells; g Confocal microscope images of H9C2 and 4T1 cells uptake DOX and PDA(DOX) for 4 h with different concentrations; h Flow cytometric analysis of apoptosis in 4T1 cells after incubated with DOX or PDA(DOX) for 24 h and Annexin V-FITC/PI double staining

Fig. 4

In vivo synergetic chemo-photothermal therapy of tumor. a, b Temperature rise curves and Thermal images of 4T1 tumor-bearing mice irradiated by 808 nm laser at a laser power of 2 W/cm² for 5 min; c Tumor growth curve within 21 days after different treatments; d Photographs of the excised tumors of mice after sacrifice; e 4T1 tumor-bearing mice images on the 0, 7, 14, and 21 days after different treatments

Fig. 5

In vivo anticancer efficiency of PDA(DOX) by chemotherapy. a Tumor growth curves within 14 days after different drug treatments; b, c Photographs and weight of the excised tumors of mice after sacrifice; d–f Body weight, blood routine test, and serum biochemical indices of chemotherapy mice after 14 days. g H&E staining images of mice tumors after different chemotherapy treatments for 14 days

Fig. 6

In vitro mitigation of DOX-induced myocardial toxicity effective. a DCF fluorescence images for intracellular detection of ROS production on H9C2 cells after incubated with DOX or PDA(DOX) for 24 h; b JC-1 fluorescence images for cell mitochondrial membrane potential detection on H9C2 cells after incubated with DOX or PDA(DOX) for 24 h

Fig. 7

In vivo mitigation of DIC effectiveness evaluation with electrocardiogram and echocardiography. a The electrocardiogram of mice in different chemotherapy groups. b, c The heart rate and QT interval of mice in different groups by electrocardiogram inspections. d The echocardiography of mice in different chemotherapy groups. e, f The left ventricular inner diameter diastole (LVIDd), left ventricular inner diameter systole (LVIDs), left ventricular ejection fraction (LVEF), and LV fractional shortening (LVFS) of mice in different groups by echocardiography inspections

Fig. 8

H&E, Masson’s trichrome, DAPI, and TUNEL staining images of mice hearts after different chemotherapy treatments for 14 days

Fig. 9

Acute toxic profiles of PDA(DOX) nanoparticles via intravenous administration. a Body weight of mice treated with PDA(DOX) within 35 days; b Organ coefficient of mice treated with PDA(DOX) after 35 days; c Blood routine test of mice after sacrifice; d Serum biochemical indices mice after sacrifice; e Major organs photographs of mice treated with PDA(DOX); f H&E staining images of mice major organs