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02 2023
:17;
105520
doi:
10.1016/j.arabjc.2023.105520

Biotin-modified hyaluronic acid double-target nanoparticles for quercetin and IR780 delivery: Fabrication, characterization, and biological properties

, , , , ,
aState Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin 300350, People’s Republic of China
bState Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang 550014, People’s Republic of China

⁎Corresponding authors. xujing611@nankai.edu.cn (Jing Xu), victgyq@nankai.edu.cn (Yuanqiang Guo)

Received: , Accepted: ,
© The Author(s) 2023
Disclaimer:
This article was originally published by Elsevier and was migrated to Scientific Scholar after the change of Publisher.

Peer review under responsibility of King Saud University.

Abstract

Abstract

Currently, the use of nanotechnology to repurpose traditional drugs has emerged as a promising strategy for cancer treatment. Quercetin (Qu), a chemotherapy molecule, has excellent antitumor activity, and IR780, a photosensitizer, possesses sound tumor phototherapy effects. However, both compounds have poor water solubility and other drawbacks that hinder their extensive clinical applications. To effectively utilize two molecules in the fight against cancer, a new multifunctional chemical-phototherapy nanoplatform with tumor target and glutathione (GSH) response was designed. By modifying hyaluronic acid (HA), the amphiphilic molecule carrying biotin and IR780 was obtained, which self-assembled to load the antitumor active molecule Qu, namely Qu@BHSI. In addition to addressing the hydrophobic issue of Qu and IR780, the prepared nanoparticles can rapidly release Qu with high concentrations of GSH present and generate heat and cytotoxic reactive oxygen species (ROS) under near-infrared light. The biological function research showed that Qu@BHSI nanoparticles had the ability to suppress the growth of A549 cells, induce cell apoptosis, stimulate ROS production in zebrafish, and inhibit angiogenesis in transgenic zebrafish. The construction of nanosystems provides new or alternative strategies and approaches for effectively repurposing classical drug molecules including photosensitizers and chemotherapy drugs.

Keywords

Nanocarrier system
Chemo-phototherapy combination
IR780
Quercetin
Tumor targeting
1

1 Introduction

Malignant neoplasms, being one of the leading causes of death worldwide, have emerged as a persistent public health challenge (Niu et al., 2019). Developing new drugs is the primary option for cancer treatment, but it involves overcoming the challenges of lengthy development cycles and exorbitant costs. Therefore, it appears to be a more efficient approach to uncover new or improved methods for utilizing classical drugs in a more effective manner and addressing their limitations, such as low solubility and lack of targeting (Tewari et al., 2019). Nanotechnology has been regarded as an emerging technology, and its application in drug delivery systems provides a new strategy for effectively repurposing traditional drugs, which brings new hope for treating tumors (López-Méndez et al., 2023). So far, scientists have utilized nanotechnology to develop various nanoplatforms, which could increase the solubility of hydrophobic drug molecules, prevent premature degradation of drugs under physiological conditions, and facilitate targeted drug delivery for controlled release. These new nanoplatforms overcome the limitations of traditional medicines and achieve the desired therapeutic effects (Wang et al., 2021; Liu et al., 2022; Yang et al., 2022; Zheng et al., 2023).

When discussing the effective reapplication of antitumor drugs, the photosensitizer IR780 with phototherapeutic effects and the natural product quercetin (Qu) with good antitumor activity have attracted our attention. IR780 is an analogue of the FDA-approved photosensitizer, indocyanine green (ICG), which exhibits excellent photothermal and photodynamic effects during phototherapy (He et al., 2019; Liu et al., 2018). However, the limited solubility of IR780 in water greatly restricts its clinical application. Qu has been regarded as a natural anticancer drug, primarily used for treating lung cancer, liver cancer, and breast cancer (Hu et al., 2017; Tian et al., 2020; Wu et al., 2013). Thus, it is urgent to discover new methods to overcome the limitations of IR780 and Qu. In addition to addressing the water solubility of Qu and IR780, another essential consideration for the effective repurposing of classic drugs is improved targeting. This often involves the use of appropriate excipients to construct well-designed targeted nanodrug-loading systems. Hyaluronic acid (HA) is a naturally occurring acidic mucopolysaccharide with abundant sources. It has good biocompatibility, low toxicity, and degradable properties (Zhang et al., 2020). More importantly, HA can specifically target the CD44 receptor (Huang et al., 2019; Dosio et al., 2016). Biotin is another biomolecule that is a necessary nutrient for maintaining natural growth, development, and health. Besides its biological activity, biotin is commonly used as a carrier for nano-drugs due to its safety and non-toxicity, which has good characteristics of targeting tumor cells, such as cervical, breast, lung, and ovarian (Deshpande & Jayakannan, 2018; Singh et al., 2017).

As mentioned above, in addition to developing new drugs to combat tumors, the efficient repurposing of traditional drugs is also a novel and effective approach to conquering tumors. Considering the promising anticancer activity of Qu and the exceptional phototherapy ability of IR780, we aim to develop a novel nanodrug-loading system that combines Qu and IR780 in a single nanosystem, specifically targeting tumors (Zhou, Y., 2021). This approach not only addresses their individual limitations but also enables an effective and safe combination of chemotherapy and phototherapy. Based on this concept, hyaluronic acid (HA) was modified with biotin to form a carrier for a dual-targeting nanosystem. Then, IR780, which has a phototherapeutic effect, was also coupled to HA to synthesize the biotin-HA-S-S-IR780 amphiphilic molecule. Subsequently, the antitumor molecule Qu was physically encapsulated through the self-assembly of the amphiphilic material biotin-HA-S-S-IR780 synthesized above. The final synthesized nanoparticles were abbreviated as Qu@BHSI. In addition to preparing and characterizing nanoparticles, the biological properties of Qu@BHSI were also investigated, including their ability to induce apoptosis and inhibit angiogenesis.

2

2 Materials and methods

2.1

2.1 Materials and reagents

Sodium hyaluronic acid (Mw, 35 kDa) was obtained from Yuanye Biotechnology Co., Ltd. (Shanghai, China). N-hydroxysuccinimide (NHS), triethylamine (Et3N), and 4-dimethylaminopyridine (DMAP) were purchased from Aladdin Biochemical Technology Co., Ltd. (Shanghai, China). Biotin, 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC), and IR780-iodide (IR780) were acquired from Tianjin Heans Biochemical Technology Co., Ltd. (Tianjin, China). 1,3-Diphenylisobenzofuran (DPBF) were purchased from Macklin Biochemical Technology Co., Ltd. (Shanghai, China). Cystamine dihydrochloride was purchased from Meryer Chemical Technology Co., Ltd. (Shanghai, China). Qu was supplied by Shanghai D&B Biotechnology Co., Ltd. (Shanghai, China). The Annexin V-FITC Apoptosis Detection Kit was provided by Beyotime Co., Ltd. (Shanghai, China). Cell tracker CM-DiI was offered by Yeasen Co., Ltd. (Shanghai, China). All other chemical reagents used were of analytical grade.

2.2

2.2 Synthesis and characterization of biotin-HA-S-S-IR780

2.2.1

2.2.1 Synthesis and characterization of cystamine-IR780

Cystamine-modified IR780 (S-S-IR780) was synthesized through a substitution reaction between the chlorine atom in IR780 and the amino group in cystine dihydrochloride. Briefly, the IR780 (240.0 mg) was mixed with cystamine dihydrochloride (324.3 mg) in a 50 mL round-bottom flask under a nitrogen atmosphere. Afterward, 20 mL of anhydrous DMSO was injected into the round-bottom flask, followed by the addition of triethylamine (1 mL). The mixture was stirred using a magnetic stirrer at room temperature until the solution changed to a blue color. After removing the solvent, the product was further extracted four times with a mixture of dichloromethane and water to remove excess triethylamine and cystine dihydrochloride. The blue solid was obtained after the solution was evaporated. The structure of S-S-IR780 was characterized by a 1H NMR experiment (Bruker AV 400 instrument, Ettlingen, Germany, 400 MHz for 1H) with deuterated DMSO‑d6 as the solvent.

2.2.2

2.2.2 Synthesis and characterization of biotin-HA

Biotin-HA was obtained through a one-step esterification process, which involved the carboxylic group of biotin reacting with the primary hydroxy groups of HA. Biotin (244 mg, 1 mmol) was dissolved in 20 mL of DMSO and mixed with EDC (155 mg, 1 mmol) and DMAP (122 mg, 1 mmol) at 50 °C for 2 h to activate the carboxyl groups of biotin. Subsequently, HA (200 mg, 0.25 mmol hydroxy group) was dissolved in 10 mL of ultrapure water and added to the above solution. The reaction proceeded at room temperature for 24 h with gentle agitation. The resulting solution was dialyzed (Mw cut-off, 3500 Da) for 3 days. After dialysis, the solution was filtered through a 0.45 μm Millipore filter and lyophilized at − 80 °C for 48 h. The structure of biotin-HA was determined by 1H NMR using deuterated DMSO‑d6: D2O = 1: 1 as the solvent.

2.2.3

2.2.3 Synthesis and characterization of biotin-HA-S-S-IR780

To synthesize the molecule biotin-HA-S-S-IR780, biotin-HA (148 mg, 0.15 mmol) dissolved in DMSO/H2O (1: 1, v/v) reacted with EDC (47 mg, 0.3 mmol) and NHS (35 mg, 0.3 mmol) for 2 h at room temperature to activate the carboxyl group of HA. Afterward, cystamine-modified IR780 (240 mg, 0.3 mmol) dissolved in DMSO was injected into the round-bottom flask. The mixture was stirred magnetically at room temperature for 24 h under a nitrogen atmosphere. After the reaction, the resulting solution was dialyzed (Mw cut-off, 12000 Da) against an excess amount of water/ethanol (1: 1, v/v) for 3 days and against distilled water for another 2 days. The structure of biotin-HA-S-S-IR780 was determined by 1H NMR using a solvent mixture of DMSO‑d6 and D2O in a 1:1 ratio.

2.3

2.3 Fabrication of Qu@BHSI

Qu-loaded biotin-HA-S-S-IR780 nanoparticles (Qu@BHSI) were prepared using the dialysis method (Jung et al., 2017). Qu (0.4 mg) was dissolved in 1 mL of methanol. The biotin-HA-S-S-IR780 amphiphilic copolymer was dispersed in methanol/water (2: 1, v/v) to afford the concentration of 2 mg/mL. Next, the Qu solution was slowly injected into the amphiphilic polymer solution, followed by sonication for 30 min to form a colloidal solution. The mixture was then dropped into ultrapure water (4 mL) in an ultrasonic ice bath and sonicated for an additional 30 min. Afterward, the solution was stirred at room temperature in the dark for 12 h. After that, the mixture was dialyzed (Mw cut-off, 3500 Da) against water for 24 h with frequent water exchanges to eliminate methanol. After dialysis, the solution of Qu@BHSI was centrifuged at 4000 rpm for 10 min to separate the unloaded Qu. The supernatant collected was filtered through a 0.45 μm membrane to obtain Qu@BHSI nanoparticles.

2.4

2.4 Characterization of Qu@BHSI

The hydrodynamic particle size, polydispersity index (PDI), and zeta potential of the Qu@BHSI were analyzed by a Zetasizer Nano ZS90 particle analyzer (Malvern, Worcestershire, UK). The absorbance of the Qu, biotin-HA-S-S-IR780, and Qu@BHSI solutions in the range of 300–1000 nm was determined by a UV–vis spectrophotometer. The morphology of Qu@BHSI was observed by transmission electron microscopy (TEM, Talos F200C, FEI, USA). The encapsulation efficiency (EE) and loading content (LC) of Qu in Qu@BHSI were determined using UV–vis absorption spectra by measuring the absorbance of free Qu.

2.5

2.5 In vitro stability of Qu@BHSI

The in vitro size stability of Qu@BHSI was measured according to the method described (Zhang et al., 2021). Briefly, Qu@BHSI was added to a PBS solution (pH = 7.4) and left in an aqueous solution at room temperature for 5 days. The stability of Qu@BHSI was investigated by monitoring the hydrodynamic diameter at various incubation times (0, 24, 48, 72, and 96 h).

2.6

2.6 Reductive release of Qu@BHSI

The disassembly of redox-sensitive Qu@BHSI in response to glutathione (GSH) in PBS (pH 7.4) was monitored using DLS measurement at 48 h. The release of Qu from Qu@BHSI was investigated using the dialysis method. Briefly, 2 mL of Qu@BHSI was transferred into a dialysis membrane (Mw cut-off, 3500 Da), which was immersed in 100 mL of the corresponding buffer solution. The buffer solutions were prepared using PBS (pH 7.4) with concentrations of 0 μM, 10 μM, and 10 mM of GSH, respectively. The mixture was then maintained at 37 °C in a shaker at 100 rpm. At regular intervals, 2 mL of medium was removed, and 2 mL of fresh PBS was added. The amount of released Qu was tested by a UV–Vis spectrophotometer. The concentration of Qu was quantified using the standard curve.

2.7

2.7 Photothermal effect in vitro

The photothermal effect of the Qu@BHSI nanoparticles was investigated by irradiating the sample with a laser. In brief, Qu@BHSI nanoparticles were diluted with distilled water to various concentrations (25, 50, 100, and 200 μg/mL), which were then added into the wells of a 12-well plate and irradiated by a 660 nm laser with a power density of 0.8 W/cm2 for 5 min. The distilled water served as the blank control. The temperature of the solution was measured at regular intervals (0, 0.5, 1.0, 1.5, 2, 2.5, 3.0, 3.5, 4.0, 4.5, and 5.0 min).

2.8

2.8 Reactive oxygen species (ROS) measurements

The spectroscopic approach using 1,3-diphenylisobenzofuran (DPBF) was applied to study the ROS generation under NIR laser irradiation (Hu et al., 2018). In brief, IR780, BHSI, and Qu@BHSI nanoparticles were diluted with water to a concentration of 50 μg/mL. Then, 30 µL of DPBF (1 mg/mL, dissolved in DMSO) was added to 2 mL of IR780, Qu@BHSI solutions, and distilled water, respectively. The group of Qu@BHSI was irradiated by a 660 nm laser (0.8 W/cm2) for 5 min. The absorbance at 420 nm was detected by a UV–Vis spectrophotometer at different times (0, 0.5, 1.0, 1.5, 2, 2.5, 3.0, 3.5, 4.0, 4.5, and 5.0 min).

2.9

2.9 In vitro antitumor assay

2.9.1

2.9.1 Cell culture

A549, HepG2, and HeLa cells were offered by the Shanghai Institute for Biological Sciences, Chinese Academy of Sciences (Shanghai, China). All cells were cultured in DMEM with 10 % FBS under humidified conditions with 5 % CO2 at 37 °C.

2.9.2

2.9.2 Cell proliferation assessment

The antiproliferative effects of Qu@BHSI combined with laser irradiation on HepG2, HeLa, and A549 cells were evaluated using the MTT assay. The cells were seeded into 96-well plates and incubated with free Qu, BHSI nanoparticles, and Qu@BHSI nanoparticles at various concentrations. After the incubation, the cells were exposed to 660 nm laser irradiation for 2 min at a power of 0.8 W/cm2. After a co-incubation period of 24 h, the cells were treated with an MTT solution for 4 h. The absorbance value was measured using a microplate reader (MK3, Thermo, Germany) at 492 nm.

2.9.3

2.9.3 Apoptosis assay

According to the instructions of the Annexin V-FITC apoptosis detection kit, the apoptosis of A549 cells induced by free Qu, BHSI nanoparticles, or Qu@BHSI nanoparticles was analyzed using flow cytometry. Briefly, the cells were treated with free Qu, BHSI nanoparticles, or Qu@BHSI nanoparticles for 6 h. Then, the cells were irradiated with a 660 nm laser for 2 min at a powder density of 0.8 W/cm2. After incubation for 24 h, the cells were washed twice with PBS and resuspended in a buffer. Subsequently, 5 μL of Annexin V-FITC and 10 μL of propidium iodide (PI) were added to the buffer, and the cells were incubated in the dark at room temperature for 20 min. The cell apoptosis was detected using flow cytometry (BD LSRFortessa, BD Biosciences, San Jose, CA, USA), and the apoptosis data were obtained using FLOWJO flow cytometry analysis software.

2.9.4

2.9.4 Intracellular ROS detection

A549 cells were stained with the ROS indicator DCFH-DA to detect the effects of free Qu, BHSI nanoparticles, or Qu@BHSI nanoparticles on intracellular ROS production. Briefly, A549 cells were inoculated into 12-well plates and cultured for 24 h. After that, they were treated with free Qu, BHSI nanoparticles, or Qu@BHSI nanoparticles for 12 h. The cells were then washed with pre-cooled PBS and stained with 10 μM DCFH-DA for 20 min at 37 °C. Then, a 660 nm laser was used to irradiate the cells at a power density of 0.8 W/cm2 for 2 min. The treated cells were harvested and washed with DMEM. Afterward, intracellular ROS levels were analyzed by flow cytometry.

2.10

2.10 In vivo antitumor assay

2.10.1

2.10.1 Zebrafish breeding

The wild-type adult AB strain zebrafish and the Tg(fli1:EGFP) transgenic zebrafish used for the biological experiments were purchased from Shanghai FishBio Co., Ltd. All procedures involving animals were approved by the Animal Ethics Committee of Nankai University (No. SYXK (JIN) 2019–0001). The care and experiments involving zebrafish were conducted in accordance with the ARRIVE guidelines. For the zebrafish embryos used in the experiments, no sex feature was observed. The zebrafish were kept in a circulating water system designed explicitly for zebrafish. The system maintained a 14-h light/10-h dark cycle, and the circulating water temperature was maintained at 28.5 °C.

2.10.2

2.10.2 In vivo ROS detection

The zebrafish model was used to assess the effects of free Qu, BHSI nanoparticles, or Qu@BHSI nanoparticles on the stimulation of ROS production. Briefly, zebrafish embryos were treated with free Qu, BHSI nanoparticles, or Qu@BHSI nanoparticles for 24 h and irradiated with a 660 nm laser at a power of 0.8 W/cm2 for 2 min. After 3 days of fertilization, zebrafish embryos were incubated with DCFH-DA (20 μg/mL) for 1 h and then washed three times with Holt buffer. Finally, the level of ROS was detected by a laser confocal microscope. The fluorescence intensity of a single zebrafish embryo was quantified by ImageJ software.

2.10.3

2.10.3 Angiogenesis inhibition experiments in transgenic zebrafish

A transgenic zebrafish angiogenesis model was used to evaluate the inhibitory effects of free Qu, BHSI nanoparticles, or Qu@BHSI nanoparticles on zebrafish angiogenesis. Transgenic zebrafish embryos fertilized for 24 h were treated with free Qu, BHSI nanoparticles, or Qu@BHSI nanoparticles for 24 h. Subsequently, a 660 nm near-infrared laser was used to irradiate each group at 0.8 W/cm2 for 2 min. After 24 h of continuous culture, the embryos were observed using a laser confocal microscope. The fluorescence intensity of each zebrafish embryo was quantitatively analyzed by ImageJ software.

3

3 Results and discussion

3.1

3.1 Synthesis and characterization of biotin-HA-S-S-IR780

The targeting and GSH-responsive molecule, biotin-HA-S-S-IR780, was synthesized through three steps (Fig. 1). Firstly, cysteamine-modified IR780 (S-S-IR780) was synthesized through a substitution reaction catalyzed by triethylamine, in which the chlorine atom of IR780 was replaced by the amino group of cysteamine. Secondly, biotin-HA was synthesized by coupling the hydroxy group of HA with the carboxylic group of biotin through a carbodiimide-catalyzed esterification reaction. Finally, S-S-IR780 was attached to biotin-HA to give the molecule biotin-HA-S-S-IR780 through an amine coupling reaction. The chemical structure of biotin-HA-S-S-IR780 was further confirmed by UV–Vis and 1H NMR analysis. As shown in Fig. S1-3, the characteristic peaks of biotin appeared at 6.74–6.76 ppm and 7.91–7.93 ppm could be clearly observed in the 1H NMR spectrum of biotin-HA, and the characteristic peaks of HA were also present, indicating the successful synthesis of biotin-HA. The characteristic peaks of IR780 appeared at 7.05–7.70 ppm and 5.80–5.84 ppm in the 1H NMR spectrum of NH2-S-S-IR780, indicating that NH2-S-S-IR780 was synthesized. In the 1H NMR spectrum of biotin-HA-S-S-IR780, the characteristic peaks of IR780 appeared at 7.05–7.37 ppm, as well as the distinct peaks of the polysaccharide appeared, which indicated that biotin-HA-S-S-IR780 had been synthesized and could be used for further experiments. Additionally, the UV–Vis spectra of IR780, S-S-IR780, biotin-HA-S-S-IR780, and biotin-HA-S-S-IR780 with 10 mM GSH were displayed in Fig. 2A. When compared to the diagnostic peak of free IR780 at 795 nm, there was a blue-shift of approximately 155 nm in the spectrum of S-S-IR780 at 640 nm, which might be attributed to the conjugation between IR780 and cysteamine. Moreover, it was observed that the diagnostic peak at 796 nm reappeared when biotin-HA-S-S-IR780 was incubated with 10 mM GSH, indicating that the disulfide bond of biotin-HA-S-S-IR780 was broken by GSH and IR780 was released. The above results confirmed the successful synthesis of biotin-HA-S-S-IR780, which could be further used as a crucial self-assembly amphiphilic molecule for constructing receptor-targeted redox-responsive drug delivery systems.

Schematic illustration of the synthesis route for biotin-HA-S-S-IR780.
Fig. 1
Schematic illustration of the synthesis route for biotin-HA-S-S-IR780.
Characterization of biotin-HA-S-S-IR780 and Qu@BHSI nanoparticles. (A) The UV spectra of IR780, IR780-S-S, biotin-HA-S-S-IR780, and biotin-HA-S-S-IR780 with 10 mM GSH. (B) Size distributions and TEM image of Qu@BHSI nanoparticles. (C) The UV spectra of Qu, biotin-HA-S-S-IR780, and Qu@BHSI nanoparticles. (D) Size distributions of Qu@BHSI nanoparticles in various concentrations of GSH for 48 h. (E) Release of Qu from Qu@BHSI nanoparticles after incubation in PBS containing 0 mM, 10 μM, or 10 mM of GSH. (F) Photothermal heating curves of different concentrations of Qu@BHSI nanoparticles in 5 min under 660 nm laser irradiation (0.8 W/cm2). (G) The residual amount of DPBF in Qu@BHSI nanoparticles after 5 min of 660 nm laser irradiation (0.8 W/cm2). Particle sizes and PDI of Qu@BHSI nanoparticles in water (H) or in PBS (I) for 4 days.
Fig. 2
Characterization of biotin-HA-S-S-IR780 and Qu@BHSI nanoparticles. (A) The UV spectra of IR780, IR780-S-S, biotin-HA-S-S-IR780, and biotin-HA-S-S-IR780 with 10 mM GSH. (B) Size distributions and TEM image of Qu@BHSI nanoparticles. (C) The UV spectra of Qu, biotin-HA-S-S-IR780, and Qu@BHSI nanoparticles. (D) Size distributions of Qu@BHSI nanoparticles in various concentrations of GSH for 48 h. (E) Release of Qu from Qu@BHSI nanoparticles after incubation in PBS containing 0 mM, 10 μM, or 10 mM of GSH. (F) Photothermal heating curves of different concentrations of Qu@BHSI nanoparticles in 5 min under 660 nm laser irradiation (0.8 W/cm2). (G) The residual amount of DPBF in Qu@BHSI nanoparticles after 5 min of 660 nm laser irradiation (0.8 W/cm2). Particle sizes and PDI of Qu@BHSI nanoparticles in water (H) or in PBS (I) for 4 days.
NIR laser-triggered antitumor activity of Qu@BHSI nanoparticles. The inhibition rates of Qu, blank BHSI nanoparticles, or Qu@BHSI nanoparticles on A549 (A), HeLa (B), and HepG2 (C) cells treated under 660 nm laser irradiation (0.8 W/cm2, 2 min). Data are expressed as mean ± SD, and all tests were conducted independently in triplicate. * p < 0.05, **p < 0.01, and ***p < 0.001 versus the control group.
Fig. 3
NIR laser-triggered antitumor activity of Qu@BHSI nanoparticles. The inhibition rates of Qu, blank BHSI nanoparticles, or Qu@BHSI nanoparticles on A549 (A), HeLa (B), and HepG2 (C) cells treated under 660 nm laser irradiation (0.8 W/cm2, 2 min). Data are expressed as mean ± SD, and all tests were conducted independently in triplicate. * p < 0.05, **p < 0.01, and ***p < 0.001 versus the control group.

3.2

3.2 Preparation and characterization of Qu@BHSI nanoparticles

Biotin-HA-S-S-IR780 owned remarkable amphiphilic properties because of the hydrophobic IR780 and hydrophilic HA in the molecule, which could self-assemble into nanoparticles in water through hydrophobic interactions. Qu, a well-known natural antitumor molecule, has been successfully encapsulated in several nanocarriers through π-π stacking and hydrophobic interactions (Shi et al., 2018; Liu et al., 2017). Based on the molecular interactions, we prepared Qu@BHSI nanoparticles using a similar method for preparing BHSI nanoparticles, in which π-π stacking and hydrophobic effects between Qu and biotin-HA-S-S-IR780 were the main driving forces.

The particle size distribution and zeta potential of Qu@BHSI nanoparticles were evaluated by dynamic light scattering (DLS). The hydrodynamic particle size of Qu@BHSI nanoparticles was approximately 100.2 nm, with a low polydispersity index (Fig. 2B), illustrating that Qu@BHSI nanoparticles can effectively penetrate tumor cells. Additionally, the zeta potential of Qu@BHSI nanoparticles was –11.5 mV, demonstrating their negative charge surface, which was attributed to the presence of deprotonated carboxylic groups on the surface of the nanoparticles. The particle size of Qu@BHSI nanoparticles was within the preferred range for tumor-enhanced permeability and retention. Additionally, the negatively charged surface ensured prolonged blood circulation time, which can be attributed to their reduced adsorption of plasma proteins (Calatayud et al., 2014). Meanwhile, the morphology of the Qu@BHSI nanoparticles was also analyzed by transmission electron microscopy (TEM) (Fig. 2B), indicating that the Qu@BHSI nanoparticles presented a spherical shape, excellent monodispersity, and a uniform size distribution. According to Fig. 2C, the absorption peaks of Qu and biotin-HA-S-S-IR780 appeared in the UV spectrum of Qu@BHSI nanoparticles, indicating that Qu was successfully encapsulated into Qu@BHSI nanoparticles. Additionally, the drug encapsulation efficiency (EE) and loading content (LC) of Qu in Qu@BHSI nanoparticles were measured to be approximately 94.6 % and 5.9 %, respectively.

3.3

3.3 Redox-induced destabilization of Qu@BHSI nanoparticles

To investigate the performance of Qu@BHSI nanoparticles in reduction reactions, the Qu@BHSI nanoparticles were co-incubated with GSH to simulate in an in vivo environment. The changes in particle sizes of Qu@BHSI nanoparticles were recorded. As shown in Fig. 2D, the size of Qu@BHSI nanoparticles increased to 197.5 nm after being exposed to 10 mM of GSH (corresponding to the environment in tumor cells) for 48 h, and the size distribution became broader. This change may be due to the cleavage of the disulfide linkages between the HA and IR780, which resulted in the disassembly and aggregation of Qu@BHSI nanoparticles. In contrast, when Qu@BHSI nanoparticles were immersed in 0 mM or 10 μM of GSH, there was no significant difference in particle size after 48 h, showing that Qu@BHSI nanoparticles remained relatively stable in the blood circulation. These results showed that Qu@BHSI nanoparticles had a GSH reduction response.

3.4

3.4 In vitro reduction-responsive release

The delivery system can rapidly release drug molecules at the desired location, thereby enhancing their therapeutic effects (Zhang et al., 2017). With the aim of evaluating the reductive release performance of Qu@BHSI nanoparticles at different GSH concentrations, the in vitro accumulative release of Qu was examined. The cumulative release curve was shown in Fig. 2E. In the absence of GSH (pH 7.4), Qu@BHSI nanoparticles released approximately 10.7 % of Qu within 12 h, and minor drug release was viewed during the subsequent 30 h. This limited release of Qu may be attributed to the encapsulation of Qu within the hydrophobic core of Qu@BHSI nanoparticles. Besides, under the condition of 10 μM of GSH, the release of Qu was comparable, in which ∼ 20.8 % of Qu was released within 12 h, followed by a slower release in the following 30 h. Additionally, in the presence of 10 mM of GSH, the release rate of Qu was significantly accelerated, in which ∼ 81.8 % of Qu was released within 12 h. This accelerated release of Qu from Qu@BHSI nanoparticles could be ascribed to the rapid rupture of disulfide bonds, which destroyed the structure of Qu@BHSI and led to the disintegration of Qu@BHSI nanoparticles, and further promoted the diffusion of Qu from the Qu@BHSI nanoparticles. The results above indicated that Qu@BHSI nanoparticles should be stable in the plasma without releasing a large amount of Qu, while Qu could be induced to release inside tumor cells rapidly. Consequently, Qu@BHSI nanoparticles are promising to be a drug delivery system with great potential to control the release of bioactive molecules and enhance therapeutic efficacy.

3.5

3.5 Photothermal activity of Qu@BHSI nanoparticles

IR780 demonstrates potential as a photothermal therapy (PTT) agent for cancer treatment, attributed to its high near-infrared (NIR) photothermal conversion efficiency (Kuang et al., 2017). Consequently, it is anticipated that IR780 confers photothermal properties to Qu@BHSI nanoparticles, enabling tumor thermal ablation and enhancing antitumor efficacy. The following experiments were performed to assess the photothermal effects of Qu@BHSI nanoparticles by examining temperature changes in solutions containing varying concentrations of IR780 under NIR laser irradiation. The resulting photothermal curves were shown in Fig. 2F. The water temperature in the blank control only increased slightly, by about 4.2 °C. In contrast to the control group, the temperature of Qu@BHSI nanoparticles rose rapidly with increasing concentration, demonstrating a dose-dependent pattern after NIR laser irradiation. Under laser irradiation for 5 min, the temperature increased from 6.5 to 12 °C as the concentration of Qu@BHSI nanoparticles increased from 50 to 300 μg/mL. From the above results, it can be inferred that Qu@BHSI nanoparticles possessed excellent photothermal ability.

3.6

3.6 Photodynamic performance of Qu@BHSI nanoparticles

DPBF probe was used to investigate the photodynamic performance of Qu@BHSI. Photodynamic therapy could generate a significant amount of ROS, which is a critical factor in destroying tumor cells (Zhu et al., 2017). ROS can react with DPBF to continuously consume DPBF (Zheng et al., 2017). Therefore, a better photodynamic effect could be indicated by the decreased residual amount of DPBF. As shown in Fig. 2G, the residual amount of DPBF as the blank control did not change under 5 min NIR laser irradiation, indicating that the NIR laser had no effect on DPBF, and the interference of the NIR laser on the experimental results could be eliminated. However, the DPBF residue of Qu@BHSI nanoparticles was approximately 50 % after 5 min NIR laser irradiation. This finding suggested that Qu@BHSI nanoparticles had the ability to generate a significant quantity of ROS for PDT.

3.7

3.7 Stability of Qu@BHSI nanoparticles

The stability of nanoparticles determines their suitability for practical applications. Therefore, we studied the stability of Qu@BHSI nanoparticles by measuring the change in particle size of Qu@BHSI nanoparticles dispersed in water or PBS. As illustrated in Fig. 2H-I, the particle size and PDI of Qu@BHSI nanoparticles dispersed in water or PBS exhibited negligible changes within 4 days. These results indicated that Qu@BHSI nanoparticles could be stored stably in water or PBS for a period of time.

3.8

3.8 In vitro antitumor activity assay of Qu@BHSI nanoparticles

3.8.1

3.8.1 NIR laser-triggered antitumor effects of Qu@BHSI nanoparticles

The antitumor effects of Qu@BHSI nanoparticles triggered by NIR laser on A549, HeLa, and HepG2 tumor cells were studied using the MTT assay. For comparison, the inhibition rates of Qu and blank BHSI nanoparticles on A549, HeLa, and HepG2 tumor cells were also studied. The results were shown in Fig. 3A-C. Qu (0.2–8 μg/mL) had weak inhibition against A549, HeLa, and HepG2 cells, and the inhibition rates were less than 20 %, which indicated that Qu had moderate antitumor activity within this concentration range. However, the blank BHSI nanoparticles exhibited a robust inhibitory effect on tumor cells, which confirmed that IR780 in the blank BHSI nanoparticles played a phototherapeutic effect under near-infrared light irradiation. In comparison to Qu and blank BHSI nanoparticles, the Qu@BHSI nanoparticles showed the best antitumor activity, indicating that IR780 and Qu in Qu@BHSI nanoparticles played a combination of chemotherapy and phototherapy. Additionally, the Qu@BHSI nanoparticles had the most potent inhibitory effect on A549 cells, while the CD44 receptors on the surface of A549 cells were overexpressed (Wang et al., 2021; Essa et al., 2022; Gao et al., 2021). This finding indirectly proved that the specific combination of HA and CD44 receptor allowed Qu@BHSI nanoparticles to aggregate more effectively at the tumor site and exert their drug effects. It also confirmed that Qu@BHSI nanoparticles had tumor-targeting capabilities.

3.8.2

3.8.2 Apoptosis of Qu@BHSI nanoparticles

As observed above, Qu@BHSI nanoparticles can target A549 cells. Therefore, the apoptosis of A549 cells affected by Qu@BHSI nanoparticles was evaluated. For comparison, the apoptosis of A549 cells stimulated by Qu and blank BHSI nanoparticles was also studied, and the results of flow cytometry were displayed in Fig. 4A-B. The apoptosis rate of the Qu group was almost no different from that of the blank control group after laser irradiation, demonstrating that Qu had weak damage effects on tumor cells, which coincided with the results shown in Fig. 3. In contrast to Qu, the apoptosis rate of blank BHSI nanoparticles increased significantly with irradiation and was about 36.07 %, indicating that IR780 in blank BHSI nanoparticles effectively promoted tumor cell death and induced apoptosis when exposed to laser irradiation. Additionally, Qu@BHSI nanoparticles exhibited the most potent apoptosis-inducing effect under laser irradiation. Approximately 38.7 % of the cells underwent apoptosis, which was higher than the apoptosis rate observed with blank BHSI nanoparticles and Qu alone. This suggested that the tumor-killing ability of blank BHSI nanoparticles was enhanced after loading Qu. The results confirmed the synergistic antitumor effects of chemotherapy and phototherapy mediated by Qu@BHSI nanoparticles.

Effect of Qu@BHSI nanoparticles on apoptosis of A549 cells irradiated by a 660 nm laser. (A) A549 cells were treated with PBS, Qu, blank BHSI nanoparticles, or Qu@BHSI nanoparticles at the specified concentration for 24 h. After 660 nm laser irradiation, the cells were stained with Annexin V-FITC and PI, and analyzed by flow cytometry. (B) Statistical analysis of apoptosis. Data are expressed as mean ± SD, and the tests were performed independently in triplicate. ***p < 0.001 versus the control group.
Fig. 4
Effect of Qu@BHSI nanoparticles on apoptosis of A549 cells irradiated by a 660 nm laser. (A) A549 cells were treated with PBS, Qu, blank BHSI nanoparticles, or Qu@BHSI nanoparticles at the specified concentration for 24 h. After 660 nm laser irradiation, the cells were stained with Annexin V-FITC and PI, and analyzed by flow cytometry. (B) Statistical analysis of apoptosis. Data are expressed as mean ± SD, and the tests were performed independently in triplicate. ***p < 0.001 versus the control group.

3.8.3

3.8.3 Intracellular ROS detection of Qu@BHSI nanoparticles

Flow cytometry was utilized to examine the photodynamic profile of Qu@BHSI nanoparticles at the cellular level, in which the level of ROS was detected by the DCFH-DA fluorescent probe. In the presence of ROS, non-fluorescent DCFH-DA can react and convert into the bright fluorescent substance 2′,7′-dichlorofluorescein (DCF) (Bao et al., 2021; Han et al., 2017). As shown in Fig. 5A, compared with the blank control group, the ROS fluorescence signal of the Qu@BHSI nanoparticles group shifted significantly to the right under NIR laser exposure, which was notably stronger than that observed in the Qu and blank BHSI nanoparticles group. Additionally, from Fig. 5B, the ROS level of the Qu@BHSI nanoparticles group was 24.95 times higher than that of the control. The results verified that Qu@BHSI nanoparticles could effectively be used for ROS generation.

Intracellular ROS generation of Qu@BHSI nanoparticles. (A) Flow cytometry analysis for intracellular ROS generation by DCFH-DA. (B) Statistical analysis of intracellular ROS generation. Data are expressed as mean ± SD, and all the tests were conducted in triplicate independently. ***p < 0.001 versus the control group.
Fig. 5
Intracellular ROS generation of Qu@BHSI nanoparticles. (A) Flow cytometry analysis for intracellular ROS generation by DCFH-DA. (B) Statistical analysis of intracellular ROS generation. Data are expressed as mean ± SD, and all the tests were conducted in triplicate independently. ***p < 0.001 versus the control group.

3.9

3.9 Qu@BHSI nanoparticles stimulated the generation of ROS in zebrafish

In vitro assays showed that Qu@BHSI nanoparticles could promote the production of intracellular ROS under laser irradiation. Moreover, the ROS production in zebrafish induced by Qu@BHSI nanoparticles was explored. The related results were clearly shown in Fig. 6. Following near-infrared laser irradiation, the green fluorescence intensity of zebrafish in groups blank BHSI group and Qu@BHSI group was significantly enhanced (Fig. 6A), which was found to be 6.01 and 6.53 times higher than that of the blank control group (Fig. 6B), respectively, displaying that blank BHSI and Qu@BHSI groups could significantly promote the production of ROS in zebrafish, which was consistent with the experimental results in vitro. The results confirmed that near-infrared light could effectively penetrate the deep tissue of zebrafish and stimulate the IR780 in Qu@BHSI nanoparticles and blank BHSI nanoparticles, allowing them to exhibit photodynamic therapy ability and generate a significant amount of ROS.

Qu@BHSI nanoparticles induced an increase in ROS levels in zebrafish. (A) Laser confocal images of zebrafish embryos treated with Holt buffer, Qu, blank BHSI nanoparticles, or Qu@BHSI nanoparticles under 660 nm laser irradiation (0.8 W/cm2, 5 min). (B) Statistical analysis of ROS production in zebrafish. Data are the expression of mean ± SD from three repeated experiments. ***p < 0.001 versus the control group.
Fig. 6
Qu@BHSI nanoparticles induced an increase in ROS levels in zebrafish. (A) Laser confocal images of zebrafish embryos treated with Holt buffer, Qu, blank BHSI nanoparticles, or Qu@BHSI nanoparticles under 660 nm laser irradiation (0.8 W/cm2, 5 min). (B) Statistical analysis of ROS production in zebrafish. Data are the expression of mean ± SD from three repeated experiments. ***p < 0.001 versus the control group.

3.10

3.10 Qu@BHSI nanoparticles inhibited zebrafish angiogenesis

The above experimental results have confirmed that Qu@BHSI nanoparticles had significant antitumor activity. Some studies have shown that tumor growth, development, invasion, and metastasis are closely related to tumoral angiogenesis (Li et al., 2021; Ferrara et al., 2003). Thus, a transgenic Tg(fli1:EGFP) zebrafish was used to explore the effects of Qu@BHSI nanoparticles on angiogenesis. The experimental data were displayed in Fig. 7. The intersegmental vessels (ISVs) of transgenic Tg(fli1:EGFP) zebrafish were shown as green fluorescence in the images. The red triangle indicated where the intersegmental vessels were broken or lost. From Fig. 7A, it can be observed that the ISVs of zebrafish embryos treated with Qu@BHSI nanoparticles were significantly disrupted under 660 nm laser irradiation in comparison to the blank control group. Additionally, the length of ISVs in the Qu@BHSI nanoparticles group was significantly shorter than that in both the blank BHSI nanoparticles group and the Qu group. The statistical data on the average length of ISVs in each group were shown in Fig. 7B. The average length of the ISVs in the Qu@BHSI nanoparticles group was 2014.5 ± 59.4 μm, which was 436.7 μm and 320.3 μm shorter than that of the Qu group (2451.2 ± 99.3 μm) and the blank BHSI nanoparticles group (2334.8 ± 69.1 μm), respectively. These results indicated that Qu@BHSI nanoparticles had the ability to inhibit angiogenesis, which was beneficial for cancer treatment.

Inhibitory effect of Qu@BHSI nanoparticles on angiogenesis in transgenic Tg(fli1:EGFP) zebrafish. (A) Laser confocal images of transgenic Tg(fli1:EGFP) zebrafish embryos treated with Holt buffer, Qu, blank BHSI nanoparticles, or Qu@BHSI nanoparticles under 660 nm laser irradiation (0.8 W/cm2, 5 min). (B) Statistical results of the average length of ISVs in each group. Data are expressed as mean ± SD from three independent tests. * p < 0.05, **p < 0.01, and ***p < 0.001 versus the control group.
Fig. 7
Inhibitory effect of Qu@BHSI nanoparticles on angiogenesis in transgenic Tg(fli1:EGFP) zebrafish. (A) Laser confocal images of transgenic Tg(fli1:EGFP) zebrafish embryos treated with Holt buffer, Qu, blank BHSI nanoparticles, or Qu@BHSI nanoparticles under 660 nm laser irradiation (0.8 W/cm2, 5 min). (B) Statistical results of the average length of ISVs in each group. Data are expressed as mean ± SD from three independent tests. * p < 0.05, **p < 0.01, and ***p < 0.001 versus the control group.

4

4 Conclusions

In the face of the enormous challenge posed by malignant tumors, in addition to developing new drugs to combat them, using nanotechnology to repurpose traditional drugs efficiently is an effective strategy. This is due to the lengthy development cycle and high cost associated with creating new drugs. In the current study, by structure modification, biotin-HA-IR780, a dual targeting molecule carrying the photosensitizer IR780, was obtained. Then, by self-assembly to load antitumor active molecule Qu, Qu and IR780 were thus integrated into a single nanocarrier system targeting tumors, which overcame the limitations of their hydrophobicity and achieved an efficient and safe combination of chemotherapy and phototherapy for cancer treatment. The subsequent biological experiments also confirmed that the nanosystem had dual effects of phototherapy and chemotherapy, which can suppress tumor cell growth, trigger tumor cell death, stimulate the production of ROS, and hinder the formation of new blood vessels. The nanocarrier system can also utilize cysteamine to couple other photosensitizers and load other active molecules, thus effectively reusing classical drug molecules.

CRediT authorship contribution statement

Linan Zhou: Methodology, Data curation, Investigation, Software, Writing – original draft. Ying Li: Data curation, Formal analysis. Zhen Lin: Data curation, Formal analysis. Xiaotang Gong: Data curation, Software, Writing – original draft. Jing Xu: Funding acquisition, Project administration, Supervision, Writing – review & editing. Yuanqiang Guo: Funding acquisition, Project administration, Supervision, Writing – review & editing.

Acknowledgments

This research was supported financially by the National Natural Science Foundation of China (Nos. 22077067 and 22177054), the project of State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University (QJJ[2022] 422), and the 111 Project B20016.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

References

  1. , , , , . Design and construction of IR780- and EGCG-based and mitochondrial targeting nanoparticles and their application in tumor chemo-phototherapy. J. Mater. Chem. B. 2021;9(48):9932.
    [Google Scholar]
  2. , , , , , , . The effect of surface charge of functionalized Fe3O4 nanoparticles on protein adsorption and cell uptake. Biomaterials. 2014;35(24):6389-6399.
    [Google Scholar]
  3. , , . Biotin-tagged polysaccharide vesicular nanocarriers for receptor-mediated anticancer drug delivery in cancer cells. Biomacromolecules. 2018;19(8):3572-3585.
    [Google Scholar]
  4. , , , , . Hyaluronic acid for anticancer drug and nucleic acid delivery. Adv. Drug Deliver Rev.. 2016;97:204-236.
    [Google Scholar]
  5. , , , , , . Dual targeting nanoparticles based on hyaluronic and folic acids as a promising delivery system of the encapsulated 4-Methylumbelliferone (4-MU) against invasiveness of lung cancer in vivo and in vitro. Int. J. Biol. Macromol.. 2022;206:467-480.
    [Google Scholar]
  6. , , , . The biology of VEGF and its receptors. Nat. Med.. 2003;9(6):669-676.
    [Google Scholar]
  7. , , , , . Preparation, characterization and in vitro antitumor activity evaluation of hyaluronic acid-alendronate-methotrexate nanoparticles. Int. J. Biol. Macromol.. 2021;166:71-79.
    [Google Scholar]
  8. , , , , , , , , , , , , , , . Upconversion nanoparticle-mediated photodynamic therapy induces autophagy and cholesterol efflux of macrophage-derived foam cells via ROS generation. Cell Death Dis.. 2017;8(6):e2864-e.
    [Google Scholar]
  9. , , , , , , . A versatile strategy to create an active tumor-targeted chemo-photothermal therapy nanoplatform: a case of an IR780 derivative co-assembled with camptothecin prodrug. Acta Biomater.. 2019;84:356-366.
    [Google Scholar]
  10. , , , , , , . Quercetin remodels the tumor microenvironment to improve the permeation, retention, and antitumor effects of nanoparticles. ACS Nano. 2017;11(5):4916-4925.
    [Google Scholar]
  11. , , , , , , . Rational design of IR820- and Ce6-based versatile micelle for single NIR laser-induced imaging and dual-modal phototherapy. Small. 2018;14(52):1802994.
    [Google Scholar]
  12. , , , , , , , , , . Hyaluronic acid nanoparticles based on a conjugated oligomer photosensitizer: Target-specific two-photon imaging, redox-sensitive drug delivery, and synergistic chemo-photodynamic therapy. ACS Appl. Bio. Mater.. 2019;2(6):2421-2434.
    [Google Scholar]
  13. , , , , , , , . Hydrophobically modified polysaccharide-based on polysialic acid nanoparticles as carriers for anticancer drugs. Int. J. Pharmaceut.. 2017;520(1–2):111-118.
    [Google Scholar]
  14. , , , , , , , . Hydrophobic IR-780 dye encapsulated in cRGD-conjugated solid lipid nanoparticles for NIR imaging-guided photothermal therapy. ACS Appl. Mater. Interfaces. 2017;9(14):12217-12226.
    [Google Scholar]
  15. , , , , , , , , . The antitumor activity and mechanism of a natural diterpenoid from Casearia graveolens. Front. Oncol.. 2021;11:688195
    [Google Scholar]
  16. , , , , , , , , , , . A multifunctional nanoparticle system combines sonodynamic therapy and chemotherapy to treat hepatocellular carcinoma. Nano Res.. 2017;10(3):834-855.
    [Google Scholar]
  17. , , , , , , , , . Hypoxia responsive nano-drug delivery system based on angelica polysaccharide for liver cancer therapy. Drug Deliv.. 2022;29(1):138-148.
    [Google Scholar]
  18. , , , , , , , , , . “Wax-Sealed” theranostic nanoplatform for enhanced afterglow imaging-guided photothermally triggered photodynamic therapy. Adv. Funct. Mater.. 2018;28(42):1804317.
    [Google Scholar]
  19. , , , , , , , , . Nanomedicine for autophagy modulation in cancer therapy: a clinical perspective. Cell Biosci.. 2023;13(1):1-17.
    [Google Scholar]
  20. , , , , , , , , . A novel chitosan-based nanomedicine for multi-drug resistant breast cancer therapy. Chem. Eng. J.. 2019;369:134-149.
    [Google Scholar]
  21. , , , , , , , . Reactive oxygen species-responsive nanoparticles based on PEGlated prodrug for targeted treatment of oral tongue squamous cell carcinoma by combining photodynamic therapy and chemotherapy. ACS Appl. Mater. Interfaces. 2018;10(35):29260-29272.
    [Google Scholar]
  22. Singh, Y., Durga Rao Viswanadham, K. K., Kumar Jajoriya, A., Meher, J. G., Raval, K., Jaiswal, S., Dewangan, J., Bora, H. K., Rath, S. K., Lal, J., Mishra, D. P., Chourasia, M. K., 2017. Click biotinylation of PLGA template for biotin receptor oriented delivery of doxorubicin hydrochloride in 4T1 cell-induced breast cancer. Mol. Pharmaceutics, 14(8), 2749–2765.
  23. , , , . Adverse drug reactions of anticancer drugs derived from natural sources. Food Chem. Toxicol.. 2019;123:522-535.
    [Google Scholar]
  24. , , , , , , . Low side-effect and heat-shock protein-inhibited chemo-phototherapy nanoplatform via co-assembling strategy of biotin-tailored IR780 and quercetin. Chem. Eng. J.. 2020;382:123043
    [Google Scholar]
  25. , , , . Facile fabrication of robust, hyaluronic acid-surfaced and disulfide-crosslinked plga nanoparticles for tumor-targeted and reduction-triggered release of docetaxel. Acta Biomater.. 2021;125:280-289.
    [Google Scholar]
  26. , , , , , , . Phenylboronic acid-conjugated chitosan nanoparticles for high loading and efficient delivery of curcumin. Carbohyd. Polym.. 2021;256:117497
    [Google Scholar]
  27. , , , , , , , , , , . Biodegradable polymeric micelle-encapsulated quercetin suppresses tumor growth and metastasis in both transgenic zebrafish and mouse models. Nanoscale. 2013;5(24):12480-12493.
    [Google Scholar]
  28. , , , , , , , , , . Multifunctional β-cyclodextrin-poly (ethylene glycol)-cholesterol nanomicelle for anticancer drug delivery. ACS Appl. Bio Mater.. 2022;5(11):5418-5431.
    [Google Scholar]
  29. , , , , , , , , , , , . Specifically increased paclitaxel release in tumor and synergetic therapy by a hyaluronic acid-tocopherol nanomicelle. ACS Appl. Mater. Interfaces. 2017;9(24):20385-20398.
    [Google Scholar]
  30. , , , , , , , , , , , . A dandelion polysaccharide and its selenium nanoparticles: Structure features and evaluation of antitumor activity in zebrafish models. Carbohyd. Polym.. 2021;270:118365
    [Google Scholar]
  31. , , , , , , , . Targeted delivery of honokiol by zein/hyaluronic acid core-shell nanoparticles to suppress breast cancer growth and metastasis. Carbohyd. Polym.. 2020;240:116325
    [Google Scholar]
  32. , , , , , , . Nano-baicalein facilitates chemotherapy in breast cancer by targeting tumor microenvironment. Int. J. Pharmaceut.. 2023;635:122778
    [Google Scholar]
  33. , , , , , , , , , , . Single-step assembly of DOX/ICG loaded lipidepolymer nanoparticles for highly effective chemophotothermal combination therapy. ACS Nano. 2017;7(3):2056-2067.
    [Google Scholar]
  34. , , , , , , . Engineering a photosensitizer nanoplatform for amplified photodynamic immunotherapy via tumor microenvironment modulation. Nanoscale Horiz.. 2021;6(2):120-131.
    [Google Scholar]
  35. , , , , , , , . Regulating near-infrared photodynamic properties of semiconducting polymer nanotheranostics for optimized cancer therapy. ACS Nano. 2017;11(9):8998-9009.
    [Google Scholar]

Appendix A

Supplementary material

Supplementary data to this article can be found online at https://doi.org/10.1016/j.arabjc.2023.105520.

Appendix A

Supplementary material

The following are the Supplementary data to this article:

Supplementary data 1

Supplementary data 1


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