Mn2+-coordinated PDA@DOX/PLGA nanoparticles as a smart theranostic agent for synergistic chemo-photothermal tumor therapy

Abstract

Nanoparticle drug delivery carriers, which can implement high performances of multi-functions, are of great interest, especially for improving cancer therapy. Herein, we reported a new approach to construct Mn²⁺-coordinated doxorubicin (DOX)-loaded poly(lactic-co-glycolic acid) (PLGA) nanoparticles as a platform for synergistic chemo-photothermal tumor therapy. DOX-loaded PLGA (DOX/PLGA) nanoparticles were first synthesized through a double emulsion-solvent evaporation method, and then modified with polydopamine (PDA) through self-polymerization of dopamine, leading to the formation of PDA@DOX/PLGA nanoparticles. Mn²⁺ ions were then coordinated on the surfaces of PDA@DOX/PLGA to obtain Mn²⁺-PDA@DOX/PLGA nanoparticles. In our system, Mn²⁺-PDA@DOX/PLGA nanoparticles could destroy tumors in a mouse model directly, by thermal energy deposition, and could also simulate the chemotherapy by thermal-responsive delivery of DOX to enhance tumor therapy. Furthermore, the coordination of Mn²⁺ could afford the high magnetic resonance (MR) imaging capability with sensitivity to temperature and pH. The results demonstrated that Mn²⁺-PDA@ DOX/PLGA nanoparticles had a great potential as a smart theranostic agent due to their imaging and tumor-growth-inhibition properties.

Keywords: PLGA nanoparticles; chemo-photothermal therapy; polydopamine; smart theranostic agent.

Figure 1

(A, C) SEM and (B, D) TEM images of (A, B) PLGA nanoparticles and (C, D) PDA@PLGA nanoparticles. XPS patterns of (E) Mn²⁺-PDA@PLGA and (F) corresponding deconvoluted Mn2p spectrum of Mn²⁺-PDA@PLGA; (F) is the enlarged view of black box in (E). Abbreviations: PDA, polydopamine; PLGA, poly(lactic-co-glycolic acid); SEM, scanning electron microscopy; TEM, transmission electron microscopy; XPS, X-ray photoelectron spectroscopy.

Figure 2

(A) T1-weighted MR images of Mn²⁺-PDA@PLGA at different concentrations of Mn²⁺ (mmol/L). (B) The relaxation rates (1/T1) of Mn²⁺-PDA@PLGA versus different concentrations of Mn²⁺. (C) In vivo T1-weighted MR images of a mouse taken before injection (upper) and 24 h postintravenous injection (bottom) with Mn²⁺-PDA@ PLGA. A brightening effect could be observed in the tumor region. The red circle is the tumor region of the mice. (D) T1-weighted MR signals in the tumor before injection and 24 h postintravenous injection with Mn²⁺-PDA@PLGA. Abbreviations: PDA, polydopamine; PLGA, poly(lactic-co-glycolic acid); MR, magnetic resonance; IV, intravenous.

Figure 3

(A) Photothermal images of Mn²⁺-PDA@PLGA suspension (200 μg/mL) after irradiation (808 nm, 1.0 W/cm²) at different times. (B) Temperature increase curves for water and Mn²⁺-PDA@PLGA solutions with an 808 nm laser at a power of 1.0 W/cm². The total irradiation time was 10 min. (C) DOX release percentage from Mn²⁺⁻PDA@DOX/PLGA at varied pH values and temperatures. (D) Mn²⁺ release percentage from Mn²⁺-PDA@DOX/PLGA at varied pH values and temperatures. Abbreviations: DOX, doxorubicin; PDA, polydopamine; PLGA, poly(lactic-co-glycolic acid).

Figure 4

(A) Relative viabilities of CT26 cells after being incubated with various concentrations of Mn²⁺-PDA@PLGA for different times. (B) Relative viabilities of CT26 cells incubated with various concentrations of Mn²⁺-PDA@PLGA and Mn²⁺-PDA@DOX/PLGA nanoparticles with or without an 808 nm laser irradiation (1.0 W/cm²) for 10 min. (C) Confocal fluorescence images of CT26 cells incubated at 24 h postincubation with Mn²⁺-PDA@DOX/PLGA. Abbreviations: DAPI, 4,6-diamidino-2-phenylindole; DOX, doxorubicin; PDA, polydopamine; PLGA, poly(lactic-co-glycolic acid).

Figure 5

In vivo photothermal therapy of the CT26 tumor bearing mice. (A) Biodistribution of Mn²⁺-PDA@DOX/PLGA in mice. ICP-AES histograms of Mn²⁺ in heart, liver, spleen, lung, kidney and tumor at 24 h postinjection with Mn²⁺-PDA@DOX/PLGA. (B) Representative photos of tumors on mice after various treatments indicated. (C) Photos of tumors from (1) control group, (2) laser only group, (3) Mn²⁺-PDA@DOX/PLGA group, and (4) Mn²⁺-PDA@DOX/PLGA + NIR group. (D) Tumor weights of each group after excision. (E) Tumor growth curves of different groups after treatment. The tumor volumes were normalized to their initial sizes. (F) The body weight after the various treatments indicated over 21 days. Abbreviations: DOX, doxorubicin; ID, injected dose; ICP-AES, inductively coupled plasma-atomic emission spectroscopy; NIR, near-infrared; PDA, polydopamine; PLGA, poly(lactic-co-glycolic acid).

Figure 6

Optical microscopy images of the main organs (heart, liver, spleen, lung and kidney) of Mn²⁺-PDA@PLGA-treated healthy Balb/c mice after histological hematoxylin and eosin staining. The mice intravenously received Mn²⁺-PDA@PLGA saline solution at different doses (12.5, 25 and 50 mg/kg) and were fed for 30 days. Scale bars of all images: 100 μm. Abbreviations: PDA, polydopamine; PLGA, poly(lactic-co-glycolic acid).

Scheme 1

Schematic diagram of synthesis process of Mn²⁺-PDA@DOX/PLGA nanoparticles. Abbreviations: DOX, doxorubicin; PDA, polydopamine; PLGA, poly(lactic-co-glycolic acid); W₁/O/W₂, water₁/oil/water₂.