Hyaluronic acid modified covalent organic polymers for efficient targeted and oxygen-evolved phototherapy

Abstract

The integration of multiple functions with organic polymers-based nanoagent holds great potential to potentiate its therapeutic efficacy, but still remains challenges. In the present study, we design and prepare an organic nanoagent with oxygen-evolved and targeted ability for improved phototherapeutic efficacy. The iron ions doped poly diaminopyridine (FeD) is prepared by oxidize polymerization and modified with hyaluronic acid (HA). The obtained FeDH appears uniform morphology and size. Its excellent colloidal stability and biocompatibility are demonstrated. Specifically, the FeDH exhibits catalase-like activity in the presence of hydrogen peroxide. After loading of photosensitizer indocyanine green (ICG), the ICG@FeDH not only demonstrates favorable photothermal effect, but also shows improved generation ability of reactive oxygen species (ROS) under near-infrared laser irradiation. Moreover, the targeted uptake of ICG@FeDH in tumor cells is directly observed. As consequence, the superior phototherapeutic efficacy of the targeted ICG@FeDH over non-targeted counterparts is also confirmed in vitro and in vivo. Hence, the results demonstrate that the developed nanoagent rationally integrates the targeted ability, oxygen-evolved capacity and combined therapy in one system, offering a new paradigm of polymer-based nanomedicine for tumor therapy.

Keywords: Covalent organic polymers; Hypoxia tumor; Photodynamic therapy; Photothermal therapy; Targeted therapy.

Scheme 1

Fabrication of polymer-based nanomedicine for targeted and oxygen-evolved phototherapy of tumor

Fig. 1

Transmission electron microscopy (TEM) images of A, B FeD and D, E FeDH. Scanning electron microscopy (SEM) images of C FeD and F FeDH. G High-angle annular dark field scanning TEM (HAADF-STEM) image and element mapping of FeDH. H Energy dispersive X-ray spectrum of FeDH. I UV–vis spectra of free ICG, FeDH, and ICG@FeDH. Inset is the photos of FeDH (left) and ICG@FeDH (right) dispersions. J Zeta potential results of different samples. K Size distributions of FeDH dispersed in different media. L Average size of FeDH in different media measured by dynamic light scattering (DLS) within 1 week

Fig. 2

a The temperature change versus irradiation time of FeDH aqueous dispersions at different concentrations. Curves. b The heating curve of ICG@FeDH, FeDH and H₂O under the same conditions (1 W/cm², 5 min). c Temperature change value and d thermal imaging photos at different time points of the corresponded samples in b. e Temperature change of ICG@FeDH dispersions exposed to photothermal heating and natural cooling cycles under 808 nm laser irradiation. f Measurement of photothermal conversion efficiency of ICG@FeDH at 808 nm

Fig. 3

a The oxygen content of different samples measured by digital oxygen meter. b Confocal laser scanning microscopy (CLSM) images of PC-3 cells after stained with RDDP for 2 h and incubated with or without FeDH for another 2 h. c UV–vis spectra of DPBF solutions mixed with (c) ICG@FeDH plus hydrogen peroxide and d ICG@FeDH under 808 nm laser irradiation for different time points. e The calculated degradation rate of DPBF based on the absorbance values at 419 nm in c, d

Fig. 4

CLSM images of PC-3 cells treated with ICG@FeD, ICG@FeDH and ICG@FeDH with free HA pre-treatment for 2 h. Blue color represents DAPI, red color represents the fluorescence of ICG. Scale bar is 40 μm

Fig. 5

a CLSM images of DCFH-DA stained PC-3 cells after treated with (i) complete culture medium, (ii) NIR laser irradiation, (iii) ICG@FeDH alone, (iv) ICG@FeD plus laser irradiation and (v) targeted ICG@FeDH plus laser irradiation. And (vi) The mean fluorescence determined from the corresponded CLSM images. b Cell viability of PC-3 cells incubated with FeDH at different concentrations for 24 h. c Cell viability of PC-3 cells treated with ICG@FeDH after different irradiation time. d Cell viability of PC-3 cells subjected to the corresponding treatments: (i) complete culture medium, (ii) NIR laser irradiation, (iii) ICG@FeDH alone, (iv) ICG@FeD plus laser irradiation and (v) targeted ICG@FeDH plus laser irradiation

Fig. 6

a The change of relative tumor volume within two weeks under different treatments. b The tumor photographs extracted from mice of different groups at the end of treatments. c The change of body weights of experimental mice of different groups in the period of treatments. d H&E staining and e Immunofluorescence staining for HIF-1α expression level of histological sections from tumor tissues in different groups. Green color in d represents HIF-1α and Blue color represents DAPI. Scale bar in c, d is 200 μm