Polydopamine Core–Shell Nanoparticles with Redox‑Responsive Polymer Shells for Targeted Drug Delivery and Synergistic Chemo‑Photothermal Therapy

Abstract

Near‑infrared (NIR) photothermal therapy (PTT) offers high tumour selectivity and minimal side‑effects, yet its clinical impact is limited by insufficient heat delivery. Here we report a core‑shell nanoparticle that combines a polydopamine (PDA) core with a disulfide‑crosslinked poly(methacrylic acid) (PMAA) shell. The PDA core delivers efficient NIR photothermal conversion, while the redox‑labile PMAA shell encapsulates doxorubicin (DOX) and releases it selectively in the reducing, acidic microenvironment of cancer cells. In vitro, DOX‑loaded PDA@PMAA nanoparticles show a synergistic inhibition of A549 cells when combined with low‑dose laser irradiation, achieving >85 % cell kill at a total drug dose of 5 µg mL⁻¹. This platform demonstrates precise, triggered drug release and enhanced chemo‑photothermal efficacy.

Introduction

PTT uses NIR‑absorbing agents to convert light into heat, ablation‑grade temperatures (>55 °C) are required for tumour necrosis while sparing normal tissue. Polydopamine (PDA) is a mussel‑inspired polymer that absorbs strongly in the NIR, exhibits 40 % photothermal conversion efficiency, and is biocompatible and biodegradable. However, single‑mode PTT cannot achieve sufficient temperature in the tumour core without damaging surrounding tissue. Combining hyperthermia with chemotherapy has emerged as a powerful strategy: heat enhances drug uptake and increases drug cytotoxicity, while chemotherapy kills cells that survive heating. To realize this synergy, we designed a smart core‑shell system where the PDA core provides photothermal conversion and the disulfide‑crosslinked PMAA shell acts as a drug reservoir that degrades in the tumour’s reductive environment (glutathione concentrations 2–10 mM vs. 20–40 µM in plasma) and in mildly acidic pH.

Materials and Methods

Materials

All reagents were analytical grade. Dopamine hydrochloride, methacryloyl chloride, glutathione, methacrylic acid (MAA), N,N’‑bis(acryloyl)cystamine (BAC), 2,2‑azobisisobutyronitrile (AIBN), and doxorubicin (DOX·HCl) were purchased from standard suppliers. Cell culture reagents were obtained from Invitrogen and Sigma‑Aldrich.

Characterization

Transmission electron microscopy (TEM) (Tecnai G2 20 TWIN) visualised morphology. Dynamic light scattering (DLS, Malvern Nano‑ZS90) measured hydrodynamic size and ζ‑potential. UV‑vis spectra were recorded on a Perkin‑Elmer Lambda 750. Fourier‑transform infrared (FT‑IR) spectra (Nicolet 6700) confirmed cross‑linking. Photothermal performance was assessed by irradiating aqueous dispersions (100 µg mL⁻¹) with an 808‑nm laser (5 W cm⁻²) for 300 s and recording temperature changes with a thermocouple (±0.1 °C). Cellular uptake and localisation were imaged by confocal laser scanning microscopy (CLSM, Leica TCS SP8 STED 3X).

Synthesis of PDA@PMAA Nanoparticles

PDA spheres were formed by oxidising 0.5 g dopamine in 90 mL H₂O/40 mL EtOH/3 mL NH₃•H₂O at 30 °C for 24 h. The PMAA shell was grown via distillation‑precipitation polymerisation: 100 mg MAA, 10 mg BAC, 3 mg AIBN dissolved in 25 mL acetonitrile, followed by addition of 50 mg PDA spheres. The mixture was heated to 100 °C, stirred for 2 h, then centrifuged and washed. By varying the PDA/MAA mass ratio (0.5–6) we tuned shell thickness (120–200 nm).

Drug Loading and Release

DOX (1 mg mL⁻¹, pH 8.0) was mixed with 10 mg of PDA@PMAA‑1 for 24 h, then centrifuged and washed. Loading content (LC) and encapsulation efficiency (EE) were calculated from UV‑vis absorbance at 480 nm. In vitro release was monitored in phosphate buffers (pH 7.4, 5.5) with/without 10 mM GSH at 37 °C, sampling every 2 h. A dialysis bag (14 kDa MWCO) held the nanoparticles; release medium was refreshed upon sampling. Release percentage was calculated as cumulative drug released divided by total loaded drug.

Cell Studies

Human embryonic kidney (HEK‑293T) and lung adenocarcinoma (A549) cells were cultured in DMEM + 10 % FBS. Cellular uptake of DOX‑loaded PDA@PMAA was observed after 1 h and 4 h incubation. Cytotoxicity was evaluated by MTT assay: cells were treated with free DOX, blank PDA@PMAA, or DOX‑loaded PDA@PMAA (10–100 µg mL⁻¹) for 24 h, with or without 808‑nm laser irradiation (5 W cm⁻², 300 s). Cell viability was expressed relative to untreated controls. Live/dead staining (Calcein‑AM) and CLSM confirmed the therapeutic outcome.

Results and Discussion

Nanoparticle Morphology and Physicochemical Properties

TEM images reveal monodisperse, spherical PDA cores (~100 nm) and PDA@PMAA particles (120–200 nm) with uniform shells. DLS shows hydrodynamic diameters of 176–349 nm, indicating a swollen polymer layer in aqueous media. ζ‑potentials shift from –26.8 mV (PDA) to –30.2 to +33.2 mV (PDA@PMAA) as shell thickness increases, reflecting carboxylate exposure. FT‑IR confirms the presence of amide I/II bands (1650/1550 cm⁻¹) from BAC and a C=O stretch at 1706 cm⁻¹ from PMAA, confirming successful cross‑linking.

Photothermal Performance

UV‑vis spectra show broad NIR absorption for all samples; PDA exhibits the highest absorbance at 808 nm. Photothermal heating experiments demonstrate that 100 µg mL⁻¹ PDA dispersion raises temperature by 41 °C, whereas PDA@PMAA‑1 reaches 56 °C, surpassing the 55 °C threshold for tumour ablation. The temperature increase correlates inversely with shell thickness, confirming that a thin shell preserves photothermal efficiency while still allowing drug loading.

Controlled Drug Release

DOX loading yields LC = 5.1 % and EE = 53.7 % for PDA@PMAA‑1, higher than PDA alone (LC = 3.7 %). In physiological buffer (pH 7.4) the release is negligible (<11 % over 24 h). In 10 mM GSH, 72.8 % DOX is released within 24 h due to disulfide bond cleavage. Acidic conditions (pH 5.5) with GSH trigger a burst release (≈87 % in 24 h) as protonated carboxyls collapse the polymer network. Photothermal irradiation (5 W cm⁻², 300 s) does not alter the release profile, indicating structural integrity during heating.

In Vitro Antitumour Efficacy

Confocal images show rapid cellular uptake of DOX‑loaded PDA@PMAA; fluorescence appears in the cytoplasm within 1 h and spreads to the nucleus by 4 h, indicating efficient endocytosis and drug release. HEK‑293T cells exhibit >90 % viability after 24 h exposure to blank PDA@PMAA‑1 at concentrations up to 100 µg mL⁻¹, confirming biocompatibility. A549 cells show dose‑dependent cytotoxicity: blank PDA@PMAA‑1 with laser reduces viability to ~54 % at 100 µg mL⁻¹; DOX‑loaded PDA@PMAA‑1 without laser reduces viability to ~38 % at the same drug dose. The combination of DOX‑loaded PDA@PMAA‑1 and laser reduces viability to ~16 % (IC₅₀ = 2 µg mL⁻¹), markedly better than either modality alone (IC₅₀ = 5.6 µg mL⁻¹ for free DOX). Live/dead staining corroborates these findings. The data confirm a synergistic chemo‑photothermal effect, enabling lower drug doses and minimal normal‑tissue damage.

Conclusion

We have engineered a polydopamine core–disulfide‑crosslinked PMAA shell nanoparticle that simultaneously offers high‑efficiency NIR photothermal conversion, redox‑responsive drug release, and excellent biocompatibility. DOX‑loaded PDA@PMAA‑1 achieves rapid, targeted release in the tumour microenvironment and, when combined with short‑duration laser irradiation, yields superior tumour cell kill (>85 %) at low drug concentrations. This multifunctional platform holds strong promise for clinical translation of combined chemo‑photothermal cancer therapy.

Availability of Data and Materials

Datasets generated during this study are available from the corresponding author upon request.