Charge Reversal Polypyrrole Nanocomplex-Mediated Gene Delivery and Photothermal Therapy for Effectively Treating Papillary Thyroid Cancer and Inhibiting Lymphatic Metastasis

Abstract

As a traditional treatment for papillary thyroid cancer (PTC), surgical resection of diseased tissues often brings lots of inconveniences to patients, and the tumor recurrence and metastasis are difficult to avoid. Herein, we developed a gene and photothermal combined therapy nanosystem based on a polypyrrole (Ppy)–poly­(ethylene imine)–siILK nanocomplex (PPRILK) to achieve minimally invasive ablation and lymphatic metastasis inhibition in PTC simultaneously. In this system, gelatin-stabilized Ppy mainly acted as a photothermal- and photoacoustic (PA)-responsive nanomaterial and contributed to its well-behaved photosensitivity in the near-infrared region. Moreover, gelatin-stabilized Ppy possessed a charge reversal function, facilitating the tight conjunction of siILK gene at physiological pH (7.35–7.45) and its automatic release into acidic lysosomes (pH 4.0–5.5); the proton sponge effect generated during this process further facilitated the escape of siILK from lysosomes to the cytoplasm and played its role in inhibiting PTC proliferation and lymphatic metastasis. With the guidance of fluorescence and PA bimodal imaging, gene delivery and Ppy location in tumor regions could be clearly observed. As a result, tumors were completely eradicated by photothermal therapy, and the recurrences and metastases were obviously restrained by siILK.

Optical diagnostic imaging and therapy for thyroid cancer

“…The following probes can all greatly improve the thermal efficacy ( Fig. 3 ) on thyroid tumor cells, achieving precise local thermal ablation of tumors with no significant cytotoxicity observed in animal experiments: Polymeric NPs with bevacizumab and IR825 conjugated on the surface (IR825@B-PPNs) [ 52 ], 131 I-radiolabeled cerebroid polydopamine nano-particles (CPDA- 131 I NPs) [ 53 ], 131 I-labeled BSA-modified CuS nanoparticles ( 131 I-BSA@CuS) [ 54 ], meso-methoxy-substituted DSPE-PEG-2000-coated boron dipyrromethene (B–OMe-NPs) [ 55 ], polypyrrole (Ppy)−poly-(ethylene imine)−siILK nanocomplex (PPR ILK ) [ 56 ], functionalized (epidermal growth factor (EGF), holo-transferrin, or lapatinib) HAOA-coated AuNPs [ 57 ], and photo-triggered Gold nanodots capped mesoporous silica nanoparticles (Au@MSNs) [ 58 ] ( Table 2 ).

Fig.

…”

“…

Fig. 3 Thermal efficacy of IR825@B-PPNs (A), CPDA- 131 I NPs (B), 131 I-BSA@CuS (C), B–OMe-NPs (D), PPR ILK (E) [ [52] , [53] , [54] , [55] , [56] ]. The temperature fluctuation curves of the indocyanine green (ICG) solution and IR825@B-PPNs after four photothermal heating cycles (A1).

…”

Research Progress of Photothermal Nanomaterials in Multimodal Tumor Therapy

“…Gene therapy can improve the efficacy of PTT by inhibiting the expression of specific heat shock proteins and overcoming the resistance of cancer cells to thermal damage ( 280 ). Xu et al ( 281 ) synthesized a polypyrrole-poly(ethyleneimine)-siILK nanocomplex (PPRILK) gene PTT nanosystem based on the siRNA of integrin-linked kinase (ILK). The results of in vivo and in vitro experiments showed that after 808-nm laser irradiation, the tumor growth of the PPRILK treatment group was significantly slower and the damage to normal tissue was minimized compared to the laser and gene therapy groups, indicating that the combination of gene therapy and PTT can effectively ablate tumors and inhibit tumor recurrence.…”

Controlled Bioactive Delivery Using Degradable Electroactive Polymers

“…5,6 Stimuli-responsive materials have been used in the development of drug delivery systems (DDSs) that can control drug release using endogenous stimuli (e.g., enzymes, pH, etc.) 7−9 and exogenous stimuli (e.g., electric fields, 10,11 infrared (IR), 12,13 light, 14,15 magnetism, 16,17 radiation, 18 temperature, 19 and ultrasound, 16 to name a few), 20 with a model DDS allowing control of the location and dosage of the drug, 8,21 Electroactive polymers (EAPs) are a class of stimuliresponsive polymers with a variety of technical and medical applications, with popular nondegradable examples including, but not limited to, polyaniline, polypyrrole, and poly(3,4ethylenedioxythiophene) (PEDOT). 11,22−24 The integration of nondegradable EAPs in medical devices, such as electrodes for sensing/stimulation, offers opportunities to optimize tissue− electrode interactions, such as their mechanical properties (minimizing mechanical mismatch) or the impedance of the electrodes (enhancing the longevity of function).…”

“…Stimuli-responsive materials have been used in the development of drug delivery systems (DDSs) that can control drug release using endogenous stimuli (e.g., enzymes, pH, etc. ) − and exogenous stimuli (e.g., electric fields, , infrared (IR), , light, , magnetism, , radiation, temperature, and ultrasound, to name a few), with a model DDS allowing control of the location and dosage of the drug, , …”