
==== Front
Heliyon
Heliyon
Heliyon
2405-8440
Elsevier

S2405-8440(24)12611-4
10.1016/j.heliyon.2024.e36580
e36580
Research Article
Engineering of dopamine conjugated with bovine serum albumin and zeolite imidazole framework: A promising drug delivery nanocarrier on lung cancer cells
Lei Chenggang
Liu Di
Zhou Qian
Ma Shengwei
Qian Haiyun lcgxym@hotmail.com
⁎
Department of Cardiothoracic Surgery, Jingzhou Hospital Affiliated to Yangtze University, No.26, Chuyuan Road, Jingzhou District, Jingzhou City, Hubei Province, 434020, China
⁎ Corresponding author. lcgxym@hotmail.com
20 8 2024
15 9 2024
20 8 2024
10 17 e3658016 2 2024
19 8 2024
19 8 2024
© 2024 The Authors
2024
https://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Modern, highly abundant materials called metal-organic structures (MOF) comprise metal ions and organic coordinating molecules and have attracted attention as potential biomedical materials due to their unusual properties. In the present study, the anticancer drug sorafenib (SF) and the Kaempferol (KM) were encapsulated in a nanocomposite made of bovine serum albumin (BA) as the core and pH-dependent zeolitic imidazolate framework-8 (ZIF) coating. To develop a multifunctional nanocarrier, polydopamine, Au3+ chelation, and gallic acid (GL) conjugation were used to build BA@SF@ZIF and BA@SF@ZIF/KM. A variety of characterisation techniques verified the success of the nanocarrier's fabrication. Studies in vitro exhibited that BA@SF@ZIF/DA/GL and BA@SF@ZIF/KM/DA/GL released their respective ligands in a pH-dependent manner due to ZIF-8. These nanocarriers' cytotoxicity and apoptotic effects were measured with the MTT evaluation. Morphological and nuclear damage staining in A549 and H1299 human lung cancer cells. The cytotoxicity investigation displayed that BA@SF@ZIF/DA/GL and BA@SF@ZIF/KM/DA/GL were more efficient than free sorafenib in A549 and H1299 cells with less toxicity in HUVECs. The DNA fragmentation of the cells was assessed by utilizing the comet assay. BA@SF@ZIF/KM/DA/GL increased ROS levels and caused mitochondrial membrane potential and DNA damage, which resulted in apoptosis. Therefore, we believe the developed smart BA@SF@ZIF/KM/DA/GL could be a promising therapeutic approach using sorafenib for lung cancer therapy.

Keywords

Polydopamine
Protein
Lorafenib
Aung cancer
Apoptosis
DNA fragmentation
==== Body
pmc1 Introduction

In 2020, lung tumours accounted for 18 fatalities per 100,000 persons and were the third most frequent malignancy, according to Global Cancer Observatory (GCO) data. NSCLC is the most common lung tumour, accounting for 85 % of cases, while SCLC accounts for just 15 % [1]. The prognosis for non-small cell lung cancer (NSCLC) remains dismal, with a 5-year survival rate of about 19 % despite breakthroughs in therapy and detection. Therefore, improved lung cancer treatments are needed to improve patient outcomes [2]. Lung cancer patients can now access various therapeutic options, including surgery, chemotherapy, radiation, targeted therapy, and immunotherapy. The effectiveness of surgery for NSCLC varies depending on the disease's stage [3]. In addition, platinum-based drugs are used in the first stages of NSCLC chemotherapy [[4], [5], [6]]. Lung cancer patients can also benefit from radiotherapy and immunotherapy, which involves using immune checkpoint inhibitors like Keytrude and Opdivo, whose mechanisms of action include targeting PD-1 or PD-L1 [7].

Sorafenib inhibits tyrosine kinases that aren't found in receptors and may be taken orally. It's the first drug approved for treating advanced hepatocellular carcinoma and is also used in chemotherapy for liver, kidney, and thyroid cancers. Specifically, sorafenib blocks the VEGFR-2/PDGFR signalling that promotes tumour cell proliferation by inhibiting the RAF kinase, a vital component of the RAF/MEK/ERK signalling pathway [8,9]. Phase I and II studies showed that sorafenib was effective against cancer in patients with advanced non-small cell lung cancer. However, sorafenib did not improve survival rates for those with NSCLC in phase III investigations [10]. That's why it's crucial to boost sorafenib's efficacy by combining it with other drugs that destroy cancer cells and are well tolerated by patients [11]. Combinations of pharmaceuticals have been used to improve the efficacy of anticancer treatments in recent years [12]. Together, these treatments shrink tumours and eradicate cancerous cells in various ways [13]. Synergistic treatments improve the bioavailability of primary therapy using related drugs, eliminate drug resistance mechanisms, or target the same or distinct biological pathways [14].

While killing cancer cells, it has minimal effect on healthy tissue. Clinical studies have shown that herbal drugs affect cellular signalling, whether used as part of a standard or adjunctive treatment plan [15]. When treating NSCLC, combining drugs that inhibit overstimulation of different stages of critical pathways is effective using a multipronged strategy. One of the most common glycosides of aglycone flavonoids is kaempferol (KM). The four hydroxyl groups in this yellow molecule are found at carbon 3, carbon 5, carbon 7, and carbon 4’, making it a tetrahydroxyflavone. Seeds, leaves, fruits, flowers, and some vegetables can all be good sources of kaempferol [16]. There is evidence that kaempferol and its glycosylated analogues have anticancer, anti-inflammatory, anti-inflammatory, anti-diabetic, antioxidant, antibacterial, and antitumor properties [17].

The outstanding physical characteristics, low toxicity, adequate clearance, simplicity of functionalization, excellent biocompatibility, and high drug-loading capacity of metal-organic frameworks (MOFs) have made them very attractive candidates for drug administration [18]. These metal-organic frameworks (MOFs) include metal nodes joined by multidentate organic linkers. They are a novel class of porous materials with exceptional promise for water purification, gas capture, drug delivery, separation, catalysis, and storage [19]. Still, several issues in the field of DDSs remain unanswered despite a great deal of study. Concerns about toxicity, ineffective cellular internalisation, uncontrolled drug release (such as burst effect), restricted loading capacity, and drug bioavailability are a few of these. MOF structures with better characteristics provide a viable solution to these problems [20]. Zeolitic imidazolate framework-8 is one of the MOF subclasses that has attracted much interest. Made up of coordination between Zn2+ and 2-methyl imidazole (2-MeIm), ZIF-8 has a high porosity, good bioavailability, and stability at a physiological pH of 7.4. Nevertheless, it breaks down in low-pH environments typical of cancer cells, allowing for regulated drug release [[21], [22], [23]]. Using bovine serum albumin as a pH-sensitive drug release carrier, we effectively loaded sulfosalicylic acid and boswellic acid into ZIF-8 nanoMOF structures in previous investigations. The unique qualities of MOFs—best represented by ZIF-8 have enormous potential for resolving current drug delivery system issues and offer a strong path towards creating effective and focused treatments [[24], [25], [26]].

One of the neurotransmitters that may have a role in the development of lung cancer is dopamine via its receptors [[27], [28], [29]]. Subfamily D1 consists of D1 and D5 receptors, whereas subfamily D2 consists of D2, D3, and D4 receptors. Dopamine receptor (DR) genes (i.e., DRD2, DRD3, and DRD4) are differentially expressed between people with nonsmall-cell lung cancer (NSCLC) and healthy individuals, and this expression profile difference can be used in the diagnosis, treatment, and management of NSCLC [[30], [31], [32]]. Several methods of tumour cell death, including apoptosis and autophagy, can be regulated by DRs, as has been established in recent investigations and triggered death and ferroptosis, which affects tumour behaviour and can slow its spread by sparking immune responses against it [33]. For this reason, it has been proposed that DR-targeting drugs now under development for disorders like schizophrenia and Parkinson's disease might prove effective in treating cancer and other forms of malignancy. The findings also suggest that DRs might be used as therapeutic targets to improve the immune response of cancer patients [29].

Bovine serum albumin (BA) is a bio-safe natural macromolecule that has seen extensive usage in drug and biochemistry due to its high biocompatibility, lack of antigenicity, and lack of toxicity [[34], [35], [36]]. Notably, the BA molecule has several functional groups and intramolecular disulphide bonds, allowing it to mix with other materials to build new drug carriers for redox processes without requiring the problematic pyridyl disulfide exchange procedure. A variety of response techniques have been implemented in tumour tissues to improve drug targeting [37]. Furthermore, endosomes and lysosomes within cells have substantially lower pH values (5.4), consistent with the observation that tumour tissues have lower extracellular pH values (pH = 6.8) than normal tissues and the circulation. This suggests that the pH-responsive nanocarrier construction essentially utilises the dynamic imine linkage [38]. In addition, BA with folic acid (FA) changed on its surface can target tumour cells and deliver anticancer drugs with pinpoint accuracy. This would significantly enhance cancer treatment while reducing harmful effects on normal cells and tissues [[39], [40], [41]].

One-pot fabrication encapsulated the BA@SF and BA@SF@KM with ZIF-8, yielding BA@SF@ZIF and BA@SF@ZIF/KM. The BA@SF@ZIF and BA@SF@ZIF/KM then polymerized in the polymerization of mussels utilizing dopamine (DA). One such commonly mentioned targeted compound is gallic acid (GL). BA@SF@ZIF/DA and BA@SF@ZIF/KM/DA were conjugated through gold (Au3+) intermediate coordination. To the best of our knowledge, the alteration of GL on ZIF-8 for lung cancer therapy is still unknown, even though various functionalizations with nanocarriers have been examined for potential specific drug delivery frameworks. The targeting capacity of all fabricated compounds towards the A549 and H1299 lung cancer cell lines was proposed, and the release behaviour of improved drug delivery.

2 Materials and methods

2.1 Materials

Sorafenib (SF) and Kaempferol (KM) were obtained from Xin Ding Pengfei Technology Development Co., Ltd (Beijing, China). Zinc chloride, gallic acid (GL), Dialysis bags (10 kDa), dimethyl sulfoxide (DMSO) and phosphate buffer saline (PBS) were purchased from Sigma-Aldrich Co. (St Louis, MO, USA). Bovine serum albumin, sodium chloride, and 2-methylimidazole were purchased from Ruixi Biological Technology Co., Ltd (Xian, China). 2,7-Dichlorodihydrofluorescein diacetate (DCFH-DA) was obtained from Solarbio (Beijing, China). Dulbecco's modified Eagle medium (DMEM), fetal bovine serum (FBS), 0.25 % trypsin-EDTA and 1 % penicillin-streptomycin were purchased from Gibco Co., Ltd. (Carlsbad, CA, USA). The mitochondrial membrane potential assay kit (Rhodamine-123), 4′,6-diamidino-2-phenylindole (DAPI), was purchased from Beyotime (Shanghai, China) and used according to the protocols provided by the manufacturers. MTT was purchased from Dalian Meilun Biotechnology Corporation (Dalian, China).

Scanning electron microscopy (SEM) (ZEISS SIGMA and Zeiss Merlin compact) was implemented to examine nanoparticle surface morphology and dispersion. Hydrodynamic sizes and zeta potentials were measured on a Zetasizer instrument (Nano ZS, Malvern). A BRUKER D8-discover XRD system characterised powder X-ray diffraction (XRD). Thermal gravimetric analysis (TGA) was accomplished using the thermogravimetric Setaram analyzer. The nanoparticles' Fourier transform infrared spectroscopy (FTIR) spectra were recorded using an FTIR spectrophotometer (Bruker, Germany) in the scan range of 400–4000 cm−1. Ultraviolet–visible (UV–vis) absorption spectra were obtained on a UV-2600 spectrometer (Shimadzu Ltd., Japan).

2.2 Fabrication of BA@SF

BA (100 mg) was immersed in NaCl solution (2 mL of 2.5 mM) for a typical synthesis. While stirring, NaOH (0.4 mL of 0.1 M) was incorporated into the solutions. The BA@SF NPs were synthesised by adding the immersed BA solution to a solution of SF (16 mg) in distilled water (DI; 8 mL) at a 10 mL/min rate while blending at 35 °C for 45 min.

2.3 Fabrication of BA@SF@KM

BA@SF@KM NPs dissolved BA (100 mg) in NaCl (2 mL of a 2.5 mM) solution. After thoroughly mixing, NaOH (0.4 mL of 0.1 M) was immersed in the BA solutions. This combination added SF (16 mg) and KM (10 mg) at a 10 mL/min rate while stirring at RT for 45 min.

2.4 Fabrication of BA@SF and BA@SF@KM incorporated ZIF-8

The BA@SF or BA@SF@KM solution fabricated in Sections 2.2, 2.3 was supplemented with Zn(NO3)26H2O (0.66 mmol (0.2 g)) immersed in DI (0.8 mL) and stirred for 10 min. After stirring at RT for 60 min, a solution containing 2-methylimidazole (2 g) immersed in DI (8 mL) was added drop by drop to this combination. We then centrifuged (15 min; 7500 rpm) and rinsed the resultant BA@SF@ZIF or BA@SF@ZIF/KM with DI a few times.

BA@SF@ZIF or BA@SF@ZIF/KM was evaluated using a UV–vis spectrometer set at 270 nm, and the encapsulation efficiency (EE; %) and drug loading capacity (DLC; %) were then figured. We determined the DLC (in percent) and EE (in percent) using prior research.

2.5 Fabrication of DA coated of BA@SF@ZIF and BA@SF@ZIF/KM (BA@SF@ZIF/DA) and (BA@SF@ZIF/KM/DA)

Mussel-influenced polymerization coats dopamine (DA) onto the BA@SF@ZIF or BA@SF@ZIF/KM surfaces, which was accomplished by ultra-sonicating BA@SF@ZIF (20 mg) or BA@SF@ZIF/KM (20 mg) in Tris-HCl solution (20 mL; pH = 8.5; 10 mM). After mixing dopamine hydrochloride (10 mg) to the distributions, the coating procedure was continued for 4 h. After forming BA@SF@ZIF/DA or BA@SF@ZIF/KM/DA, we centrifuged and DI-washed the mixture three times.

2.6 Changes of BA@SF@ZIF/DA and BA@SF@ZIF/KM/DA with GL

An Au-mediated coordination reaction could attach GL to BA@SF@ZIF/DA or BA@SF@ZIF/DA/KM/DA. This conjugation occurred by dispersing BA@SF@ZIF/DA (10 mg) or BA@SF@ZIF/KM/DA (10 mg) into Tris-HCl (10 mL; pH = 8.5; 10 mM). After adding gold (III) chloride (0.15 mL) solutions, the distributions were blended for an hour. The mixture was then stirred for 5 h after 30 mg of GL was added to it. To separate the complicated NPs, centrifugation and several DI washes were used and were designated as BA@SF@ZIF/DA/GL and BA@SF@ZIF/KM/DA/GL.

2.7 Fabrication of ZIF-8

Mixing Zn(NO3)26H2O (0.66 mmol of 0.2 g) into DI (0.8 mL) for 5 min yields solutions. Then, while stirring at RT for 60 min, a solution containing 2-methylimidazole (2 g) dissolved in DI (8 mL) was added drop by drop to this combination. Separation and several DI washes were performed on the resultant ZIF-8. The material was dried at 65 °C for 12 h [23].

2.8 Drug release pattern

Different in vitro conditions were used to evaluate drug release to precisely clarify the designed drug delivery devices trigger drug release. The dialysis bag was filled with phosphate buffer solution (10 mL) at pH = 7.4 and 5.0 and sealed with BA@SF@ZIF/DA/GL (5 mg) or BA@SF@ZIF/KM DA/GL (5 mg) to investigate drug release characteristics. Under guidelines for dissolution testing of parenteral goods, the dialysis bag was immersed in the buffer solution at 100 rpm at 37 °C [42].

2.9 Cell culture and MTT analysis

Human lung cancer A549 and H1299 cells and human umbilical vein endothelial cells (HUVEC) were obtained from the American Type Culture Collection (ATCC, Manassas, VA, USA). All the media were supplemented with 90 % DMEM, 10 % FBS, and 1 % penicillin-streptomycin. These cell lines were cultured at 37 °C in a humidified and 5 % CO2 atmosphere.

The cell viability of lung cancer A549 and H1299 and HUVECs were studied by 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) assay. Typically, 0.1 mL of A549 and H1299 cells in complete medium were planted in 96 well plates at a density of 0.5 × 105 cells/mL and allowed to adhere at 37 °C for 24 h. After that, the culture media were restored with 1.0 mL of fresh DMEM medium with SF, BA@SF@ZIF/DA/GL and BA@SF@ZIF/KM/DA/GL (1–10 μg/mL) for 24 h. After 24h incubation at 37 °C, 10 μL of MTT (5.0 mg/mL in PBS) was added into each well, and the cells were incubated for 4.0 h. After that, the culture medium was replaced with 150 μL of DMSO to dissolve the resulting formazan crystals [[43], [44], [45], [46], [47]]. The absorbance was recorded at a wavelength of 490 nm using a microplate reader (Synergy H1, BioTek Instruments, USA).

2.10 Dual staining

For cellular morphological changes assay, A549 and H1299 cells were seeded in 6-well plates (1.5 × 103 cells per well), cultured overnight and incubated with IC50 concentrations of PBS, SF, BA@SF@ZIF/DA/GL and BA@SF@ZIF/KM/DA/GL for 24 h. The next day, the cells were washed with PBS three times [[48], [49], [50], [51]]. They were then treated with AO-EB Kit and analyzed with the fluorescence microscope.

2.11 DAPI staining

For cellular nuclear damage assay, A549 and H1299 cells were planted in 6-well plates (1.5 × 103 cells per well), cultured overnight and incubated with IC50 concentrations of PBS, SF, BA@SF@ZIF/DA/GL and BA@SF@ZIF/KM/DA/GL for 24 h. The next day, the cells were washed with PBS three times [[52], [53], [54], [55], [56]]. They were then treated with DAPI and analyzed with a fluorescence microscope.

2.12 Propidium iodide (PI) staining

For cellular apoptosis assay, A549 and H1299 cells were planted in 6-well plates (1.5 × 103 cells per well), cultured overnight and incubated with IC50 concentrations of PBS, SF, BA@SF@ZIF/DA/GL and BA@SF@ZIF/KM/DA/GL for 24 h. The next day, the cells were washed with PBS three times [57]. They were then treated with PI and analyzed with a fluorescence microscope.

2.13 Comet assay

For cellular damage assay, A549 and H1299 cells were planted in 6-well plates (1.5 × 103 cells per well), cultured overnight and incubated with IC50 concentration of PBS, SF, BA@SF@ZIF/DA/GL and BA@SF@ZIF/KM/DA/GL for 24 h. The next day, the cells were washed with PBS three times. They were then treated with PI and analyzed with a fluorescence microscope. The cells were gathered, and the ratio of DNA damage was revealed using comet assay as in previous reports [58].

2.14 Cell adhesion assay

For the detection of cell adhesion assay, A549 and H1299 cells were seeded in 6-well plates (1.5 × 103 cells per well), cultured gelatin-coated plate along with the DMEM medium overnight and incubated with IC50 concentration of PBS, SF, BA@SF@ZIF/DA/GL and BA@SF@ZIF/KM/DA/GL for 24 h. The next day, the cells were washed with PBS three times [58]. They were then treated with trypan blue and analyzed with a fluorescence microscope.

2.15 Measurement of caspase activity

The ratio of caspase-3, caspase-8, and caspase-9 activities in the PBS, SF, BA@SF@ZIF/DA/GL and BA@SF@ZIF/KM/DA/GL for 24 h A549 and H1299 cells were perceived using the caspase assay kits as previous reports [59].

2.16 Measurement of intracellular reactive oxygen species (ROS) level

For intracellular ROS accumulation assay, A549 and H1299 cells were seeded in 6-well plates (1.5 × 103 cells per well), cultured gelatin-coated plate along with the DMEM medium overnight and incubated with IC50 concentration of PBS, SF, BA@SF@ZIF/DA/GL and BA@SF@ZIF/KM/DA/GL for 24 h. The next day, the cells were washed with PBS three times [46]. They were then treated with DCFH-DA and analyzed with a fluorescence microscope.

2.17 Mitochondrial membrane potential (MMP)

For mitochondrial membrane assay, A549 and H1299 cells were seeded in 6-well plates (1.5 × 103 cells per well), cultured gelatin-coated plate along with the DMEM medium overnight and incubated with IC50 concentration of PBS, SF, BA@SF@ZIF/DA/GL and BA@SF@ZIF/KM/DA/GL for 24 h. The next day, the cells were washed with PBS three times [47]. They were then treated with Rhodamine-123 (Rh-123) and analyzed with a fluorescence microscope.

2.18 Statistical analysis

All data are displayed as means ± standard deviations (SD). Statistical analysis was accomplished by one-way ANOVA. Significant group variations were indicated by *p < 0.05, **p < 0.01, and ***p < 0.001 respectively. p < 0.05 was considered statistically significant in all analyses.

3 Results and discussion

3.1 Fabrication and characterizations of NPs

We effectively synthesised using a one-pot method to fabricate MOFs that coat their targets. The BA@SF and BA@SF@KM interrelated with Zn2+ ions to fabricated coordination samples, and MOF rapidly arose upon the incorporation of the binding agent 2-methylimidazole. Synthesised BA@SF@ZIF and BA@SF@ZIF/KM were surface-modified with dopamine, and then GL was conjugated to them using complexation of an Au3+ ions procedure to get BA@SF@ZIF/DA/GL and BA@SF@ZIF/KM/DA/GL. We could examine the synthesised MOF by scanning electron microscopy (SEM). Nanoscale BA@SF@ZIF and BA@SF@ZIF/KM frameworks were effectively developed, with particle diameters at 350–450 nm (Fig. 1).Fig. 1 Morphological investigation of nanoparticles. SEM images of BA@SF@ZIF (scale bar is 100 nm), BA@SF@ZIF/KM (scale bar is 100 nm), BA@SF@ZIF/DA/GL (scale bar is 500 nm) and BA@SF@ZIF/KM/DA/GL ((scale bar is 500 nm)).

Fig. 1

The shape of BA@SF@ZIF did not significantly deviate from that of unloaded ZIF-8 (Fig. 1), which displayed a standard hexagonal configuration. SEM scans of BA@SF@ZIF/DA/GL and BA@SF@ZIF/KM/DA/GL prove their surfaces are rougher and have better crystallinity after GL conjugation (Fig. 1). BA@SF@ZIF/GL and BA@SF@ZIF/KM/GL, on the other hand, appear to have kept their original forms.

For BA@SF@ZIF and BA@SF@ZIF/KM, the SF encapsulation efficiency (%) and loading capacity (%) were around 20.50 % and 77.50, respectively (Fig. 2A). Approximately 20.50 % of the SF loading capacity and 77.50 % of the encapsulation efficiency were achieved for 5-Fluorouracil-GEM@MIL-100, as shown in Fig. 2A.Fig. 2 A) Drug loading capacity and Encapsulation efficiency of DF loading in BA@SF@ZIF and BA@SF@ZIF/KM. B) TGA curves of the ZIF-8, BA@SF@ZIF, BA@SF@ZIF/KM, BA@SF@ZIF/DA, BA@SF@ZIF/KM/DA, BA@SF@ZIF/DA/DL, and BA@SF@ZIF/KM/DA/DL.

Fig. 2

TGA tests were performed on all fabricated samples to check their thermal stabilities (Fig. 2B). The TGA curve showed three distinct weight loss in ZIF-8. First, solvent molecules evaporated at temperatures between 180 and 250 °C, resulting in a weight loss of 18 %. Weight loss of 25 % happened during the second time, which ensued between 255 and 650 °C and was caused by the ZIF-8 and the 2-methylimidazole carbonization molecules. By the end of the third stage, between 650 and 900 °C, all organic residues had been removed, zinc oxide had formed, and overall weight loss had achieved 87 %. The TGA bends were fabricated for BA@SF@ZIF and BA@SF@ZIF/KM (Fig. 2B) and revealed weight loss of 24 % and 29 %, respectively, in the 190–260 °C temperature reach, attributable to the elimination of ZIF-8. At 600 °C, the samples underwent a weight loss of 50 % due to the breakdown of organic components. Weight loss of around 10 % was accompanied by temperature ranges in the 30–300 °C TGA curve of the BA@SF@ZIF/DA and BA@SF@ZIF/KM/DA due to removing the H2O molecules. ZIF-8 structural breakdown and organic content removal led to 38 % and 65 % weight loss at 600 and 900 °C, respectively. TGA data reveal a constant weight reduction of 45 % and 25 %, from 30 to 90 °C, owing to the elimination of organic solvents, as seen by the considerable differences between the TGA curve of BA@SF@ZIF/DA/GL and BA@SF@KM@ZIF/DA/GL. Fig. 2B shows that weight is lost due to the disintegration of BA@SF@ZIF/DA/GL and BA@SF@ZIF/KM/DA/GL frameworks between 100 and 200 °C. In addition, between 200 and 400 °C, BA@SF@ZIF/DA/GL and BA@SF@KM@ZIF/DA/GL decompose, losing around 40 % and 30 % of their weights, respectively, which may be correlated with the disappearance of BA@SF@ZIF or BA@SF@KM and layers DA/GL in the compounds' structures. The breakdown of organic samples may also be responsible for the char residue's appearance between 400 and 800 °C.

X-ray diffraction (XRD) analysis was performed on ZIF-8, BA@SF@ZIF/DA/GL, and BA@SF@ZIF/KM/DA/GL crystal phases (Fig. 3A). In the ZIF-8 single-phase high crystalline (JCPDS = 00-061-1035), the diffraction peaks at 7.34, 10.41, 12.73, 14.72, 16.45, and 18.05° are attributed to the (0 1 1), (0 0 2), (1 1 2), (0 2 2), (0 1 3), and (2 2 2) planes, respectively. X-ray diffraction (XRD) analysis of the fabricated BA@SF@ZIF/DA/GL and BA@SF@ZIF/KM/DA/GL framework reveals that they share the same structure as ZIF-8 (Fig. 3A), indicating that the ZIF-8 crystal structure was unaffected by the addition of the drug and the other organic molecules. However, organic and drug compounds in the BA@SF@ZIF/DA/GL and BA@SF@ZIF/KM/DA/GL structures lowered the peak strengths in the corresponding XRD profile compared to those of bare ZIF-8.Fig. 3 A) Powder X-ray diffraction profile of ZIF-8, BA@SF@ZIF/DA/DL, and BA@SF@ZIF/KM/DADL. B) FT-IR analysis of ZIF-8, BA@SF@ZIF, BA@SF@ZIF/KM, BA@SF@ZIF/DA, BA@SF@ZIF/KM/DA, BA@SF@ZIF/DA/DL, and BA@SF@ZIF/KM/DA/DL.

Fig. 3

Fig. 3B shows the results of an FTIR spectroscopy analysis of the structural modifications and interaction of functional groups utilised to build drug delivery frameworks. ZIF-8 was synthesised entirely, as evidenced by all the typical peaks in its FTIR spectrum. In the spectral profile of ZIF-8, the band at 1575 and 1410 cm−1 belonged to the C=N, the band at 1010 cm−1 was accredited to the imidazole group stretch (C–N), the vibration bands of N–H groups were observed at 1170 and 1180 cm−1, and the band at 1340 cm−1 corresponded to benzene ring elongation (Fig. 3B). The 625 and 655 cm−1 peaks may relate to sp2 aromatic bending, whereas the bands between 910 and 1330 cm−1 may relate to in-plane ring bending. The peak at 545 cm−1 is characteristic of the Zn–N stretching coordination bond during the synthesis of ZIF-8 between N atoms of 2-methylimidazole and Zn2+ ions. For BA@SF@ZIF and BA@SF@ZIF/KM, the BA amide II (N–H bond) structure is found at 1545 cm−1. N–H vibrations are indicated by the peak between 1520 and 1660 cm−1, whereas hydroxyl groups are indicated by the peak between 3195 and 3580 cm−1. The hydroxyl groups C–O vibration bonds in the organic molecules are responsible for forming a new band at 1090 cm−1 when incorporating drug molecules and BA with ZIF-8 and its GL and DA alterations (Fig. 3B). The vibration C–O bond of GL and DA, as well as the O–H vibration, have caused several new peaks to appear in 1000–1710 cm−1 of the BA@SF@ZIF/DA, BA@SF@ZIF/KM/DA, and BA@SF@ZIF/DA/GL. The analyzed FTIR spectra show that they were synthesised effectively (Fig. 3B).

As shown in Fig. 4, zeta potential measurements were used to ascertain the surface charges of the finished drug delivery systems. The amine groups in the BA structure give the synthesised BA@SF@ZIF and BA@SF@ZIF/KM zeta potentials positively charged surfaces with +32.5 mV and +30.24 mV, respectively. In contrast, the dopamine molecule's phenolic groups give the hybrid NPs' outer surfaces a negative charge, with zeta potentials of −25.02 mV and −28.19 mV. The surface charges of BA@SF@ZIF/DA/GL and BA@SF@ZIF/KM/DA/GL enhanced to negatively charged zeta potential of −31.45 mV and −33.85 mV, respectively, when GL conjugations, which includes a significant volume of –OH groups in its structural morphology. These drug delivery methods have more negative zeta potential values, which suggests they will be more stable in the body.Fig. 4 Zeta potentials of the BA@SF@ZIF, BA@SF@ZIF/KM, BA@SF@ZIF/DA, BA@SF@ZIF/KM/DA, BA@SF@ZIF/DA/DL, and BA@SF@ZIF/KM/DA/DL.

Fig. 4

3.2 Drug release profile

The release behaviour of SF in BA@SF@ZIF/DA/GL and BA@SF@ZIF/KM/DA/GL was studied after their successful fabrication was verified. Fig. 5A and B shows the kinetics of SF release from BA@SF@ZIF/DA/GL and BA@SF@ZIF/KM/DA/GL under varying pH conditions. The designed drug delivery devices were found to exhibit pH-dependent SF release behaviour. While 65 % and 66 %, respectively, were released from BA@SF@ZIF/DA/GL and BA@SF@ZIF/KM/DA/GL in the initial 6 h and acidic milieu (PBS, pH = 5.0), the ratio of SF released at the pH milieu (PBS, pH = 7.4) at the same period was 4.5 % and 8.0 %, respectively. SF release from BA@SF@ZIF/DA/GL and BA@SF@ZIF/KM/DA/GL at pH = 5.0 rose 77 % and 79 %, respectively, at 12 h, but at physiological pH circumstances, the corresponding values were only 8.0 % and 9.5 %. At 12 h, the SF release was consistent at both pHs and remained constant for the next 48 h. The release of ZIF-8-encapsulated SF was maximised at a pH = 5.0 under the solubility of ZIF-8 and the breaking of the coordination link between imidazole and Zn2+ under acidic pH conditions. SF's more hydrophilic morphology in an acidic milieu than in a neutral milieu may enhance its release under acidic conditions. Drug delivery methods optimised for the higher acidic circumstances of the tumour environment rather than the neutral pH environment of normal tissues were shown to be much more effective in applying the drug.Fig. 5 The pH-responsive SF release from BA@SF@ZIF/DA/DL and BA@SF@ZIF/KM/DA/DL. Bars represent the mean ± standard deviation of individual experiments performed in triplicate.

Fig. 5

3.3 Assessment of the cytotoxicity

MTT analysis measured the cytotoxic impacts of SF and KM-loaded nanocarriers on A549 and H1299 cell lines (Fig. 6). The results demonstrated that SF released from pH-responsive nanocarriers displayed more cytotoxicity in A549 cells at all doses over 24 h than SF alone. Nearly 45 %, 63 %, and 56 % of apoptosis, respectively, in A549 cells were fabricated by SF alone, BA@SF@ZIF/DA/GL, and BA@SF@ZIF/KM/DA/GL at 5 μg/mL (Fig. 6). Moreover, cytotoxicity in HUVEC cells was reduced at 1, 5, and 10 μg/mL when SF-loaded pH-responsive nanocarriers were used instead of SF alone (Fig. 6). The combination of BA@SF@ZIF/DA/GL and BA@SF@ZIF/KM/DA/GL was less hazardous to HUVEC cells while being more successful in treating A549 cells than SF alone. Some ZIF-8-based NPs have been studied for their anticancer effects in various cancer cell lines, and the results have been published. Our findings are the first to show that SF-loaded nanocarriers are more cytotoxic than SF alone in A549 and H1299 cells at lower doses. BA@SF@ZIF/DA/GL also outperformed BA@SF@ZIF/KM/DA/GL in A549 and H1299 cells. The characteristics of various breast cancer cell lines may account for the varying degrees to which these nanocarriers are effective in A549 and H1299 cells.Fig. 6 The in vitro cytotoxicity of free SF, BA@SF@ZIF/DA/DL, and BA@SF@ZIF/KM/DA/DL treated with A549 and H1299 lung cancer cells and non-cancerous HUVEC cells for 24 h. Bars represent the mean ± standard deviation of individual experiments performed in triplicate. GraphPad Prism 8.0 was used to evaluate statistical significance. P-values <0.05, 0.01, and 0.001 were considered statistically significant diﬀerence and marked with *, **, and ***, respectively.

Fig. 6

3.4 BA@SF@ZIF/KM/DA/GL increased the apoptotic cell death

Apoptosis is an event of organized cell death, and one of the most promising strategies for treating most cancers today is to trigger apoptosis. The most common and efficient kind of cell death that does not cause inflammation or harm to neighbouring normal cells is apoptosis. Several researchers have examined apoptosis as a potentially effective therapeutic strategy for cancer treatment. Apoptosis is identified by specific biochemical and morphological changes in dying cells, such as membrane blebbing, nuclear fragmentation and condensation, shrinkage, and loss of adhesion. In the presence of anticancer drugs, cancer cells often undergo apoptosis, and if the treatment is harmful to normal cells, normal cells may become necrotic. The ability to distinguish between apoptotic and normal cells was shown to be facilitated by the dual staining (AO/EB) method. To detect and quantify the degree of apoptotic cell death using a fluorescence microscope, the tumour cells are stained with AO/EB, PI, and DAPI. Living and non-living organisms can absorb the AO dye, releasing green fluorescence when associated with RNA and red fluorescence when interpolating with DNA. The EB dye could only be absorbed by inanimate objects, such as DNA strands, which would show red fluorescence. Several fluorescent staining techniques were used to evaluate the ability of IC50 concentration of SF, BA@SF@ZIF/DA/GL and BA@SF@ZIF/KM/DA/GL to induce lung cancer A549 and H1299 cells. A549 and H1299 treated with SF, BA@SF@ZIF/DA/GL, and BA@SF@ZIF/KM/DA/GL showed enhanced fluorescence, as confirmed by AO/EB dual staining results.

Using AO/EB staining, the apoptosis-inducing potential of IC50 concentration of SF, BA@SF@ZIF/DA/GL, and BA@SF@ZIF/KM/DA/GL was investigated, shown in Fig. 7. Fig. 7 demonstrated that the control cells had more green fluorescence, a sign of alive cells devoid of apoptotic processes. Nevertheless, the A549 and H1299 cells treated with formulated SF, BA@SF@ZIF/DA/GL, and BA@SF@ZIF/KM/DA/GL (IC50 concentration) demonstrated enhanced yellow/orange fluorescence, indicating a higher quantity of apoptotic cells. These results confirmed that the A549 and H1299 cells may undergo apoptosis in response to the BA@SF@ZIF/KM/DA/GL therapy.Fig. 7 Fluorescence images of A549 and H1299 cells with the AO-EB staining after treatment with free SF, BA@SF@ZIF/DA/DL, and BA@SF@ZIF/KM/DA/DL. Scale bar 100 μm. Bars represent the mean ± standard deviation of individual experiments performed in triplicate. GraphPad Prism 8.0 was used to evaluate statistical significance. P-values <0.001 were considered statistically significant diﬀerence and marked with ***, respectively.

Fig. 7

3.5 BA@SF@ZIF/KM/DA/GL altered the nuclear morphology

The A549 and H1299 were treated with IC50 concentration of SF, BA@SF@ZIF/DA/GL and BA@SF@ZIF/KM/DA/GL showed enhanced blue fluorescence, indicating significant nuclear alterations, according to DAPI staining. The A549 and H1299 cells treated with SF, BA@SF@ZIF/DA/GL, and BA@SF@ZIF/KM/DA/GL showed elevated red fluorescence, which was consistent with apoptotic cell death in the A549 and H1299 cells, according to the results of AO-EB staining. These results unequivocally demonstrate that the formulated SF, BA@SF@ZIF/DA/GL, and BA@SF@ZIF/KM/DA/GL treatments may induce apoptosis in A549 and H1299 cells.

DAPI staining was used to examine IC50 concentration of SF, BA@SF@ZIF/DA/GL, and BA@SF@ZIF/KM/DA/GL on the nuclear morphology of the A549 and H1299 cells, which are shown in Fig. 8. The control cells showed less blue fluorescence, indicating no nuclear changes. On the other hand, A549 and H1299 cells treated with IC50 concentration of formulated SF, BA@SF@ZIF/DA/GL, and BA@SF@ZIF/KM/DA/GL showed enhanced blue fluorescence, a sign of significant nuclear alterations that ultimately lead to cell death.Fig. 8 Fluorescence images of A549 and H1299 cells with the DAPI staining after treatment with free SF, BA@SF@ZIF/DA/DL, and BA@SF@ZIF/KM/DA/DL. Scale bar 100 μm. Bars represent the mean ± standard deviation of individual experiments performed in triplicate. GraphPad Prism 8.0 was used to evaluate statistical significance. P-values <0.001 were considered statistically significant diﬀerence and marked with ***, respectively.

Fig. 8

3.6 BA@SF@ZIF/KM/DA/GL improved the apoptotic cell morphology

The morphology of apoptotic cells in A549 and H1299 treated with IC50 concentration of SF, BA@SF@ZIF/DA/GL and BA@SF@ZIF/KM/DA/GL is shown in Fig. 9. The dull red glow the control cells displayed indicates no apoptotic cell death. Remarkably, the A549 and H1299 cells treated with IC50 concentration of SF, BA@SF@ZIF/DA/GL, and BA@SF@ZIF/KM/DA/GL showed enhanced red fluorescence, indicating that the A549 and H1299 cells had undergone apoptotic cell death. This result shows that In A549 and H1299 cells, SF, BA@SF@ZIF/DA/GL, and BA@SF@ZIF/KM/DA/GL treatments may cause apoptotic cell death.Fig. 9 Fluorescence images of A549 and H1299 cells with the PI staining after treatment with free SF, BA@SF@ZIF/DA/DL, and BA@SF@ZIF/KM/DA/DL. Scale bar 100 μm. Bars represent the mean ± standard deviation of individual experiments performed in triplicate. GraphPad Prism 8.0 was used to evaluate statistical significance. P-values <0.001 were considered statistically significant diﬀerence and marked with ***, respectively.

Fig. 9

3.7 BA@SF@ZIF/KM/DA/GL increased the nuclear damage

The comet assay result is shown in Fig. 10 and confirms that nuclear damage in the A549 and H1299 cells was caused by IC50 concentration of SF, BA@SF@ZIF/DA/GL, and BA@SF@ZIF/KM/DA/GL. The absence of tail development in the control cells indicates that there has been no nuclear damage. However, a distinct tail formation was observed in the IC50 concentration of formulated SF, BA@SF@ZIF/DA/GL and BA@SF@ZIF/KM/DA/GL treated A549 and H1299 cells. This indicates that SF triggered the nuclear damage in the A549 and H1299 cells, BA@SF@ZIF/DA/GL, and BA@SF@ZIF/KM/DA/GL.Fig. 10 DNA fragmentation by comet assay images A549 and H1299 cells with the AO-EB staining after treatment with free SF, BA@SF@ZIF/DA/DL, and BA@SF@ZIF/KM/DA/DL. Scale bar 100 μm.

Fig. 10

3.8 BA@SF@ZIF/KM/DA/GL decreased the cell adhesion

Trypan blue staining was used to determine the degree of cell adhesion in the A549 and H1299 treated with SF, BA@SF@ZIF/DA/GL, and BA@SF@ZIF/KM/DA/GL. The results are shown in Fig. 11. Increased microscopic inspection of the control cells revealed better cell adhesion. On the other hand, reduced cell adhesion was demonstrated by the A549 and H1299 cells that were given IC50 concentrations of SF, BA@SF@ZIF/DA/GL, and BA@SF@ZIF/KM/DA/GL. This result showed that the A549 and H1299 cells' adhesion was reduced by the formed SF, BA@SF@ZIF/DA/GL, and BA@SF@ZIF/KM/DA/GL.Fig. 11 Cell adhesion by crystal violet staining images A549 and H1299 cells with the AO-EB staining after treatment with free SF, BA@SF@ZIF/DA/DL, and BA@SF@ZIF/KM/DA/DL. Scale bar 100 μm. Bars represent the mean ± standard deviation of individual experiments performed in triplicate. GraphPad Prism 8.0 was used to evaluate statistical significance. P-values <0.001 were considered statistically significant diﬀerence and marked with ***, respectively.

Fig. 11

3.9 BA@SF@ZIF/KM/DA/GL decreased the MMP level

Chemotherapeutic drugs cause oxidative stress in the mitochondria, which damages the mitochondrial membrane and releases nuclear components and oxidative signals into the cytoplasm and nucleus. On the other hand, ROS-mediated oxidative stress causes a dysregulation of mitochondrial activities and initiates the intrinsic apoptotic signalling pathway, which is dependent on p53. The Δψm was evaluated in this work using the rhodamine 123 staining technique, and the outcomes are displayed in Fig. 12. The A549 control cells had a high fluorescence intensity, signifying their health. Still, the A549 and H520 cancer cells treated with BA@SF@ZIF/DA/GL and BA@SF@ZIF/KM/DA/GL displayed a lower fluorescence intensity, suggesting a reduction in the inner Δψm permeabilization. An IC50 concentration of BA@SF@ZIF/DA/GL and BA@SF@ZIF/KM/DA/GL concentration was shown to attenuate the fluorescence strength, which can be linked to the depolarization of Δψm, which is caused by an increase in ROS formation and the subsequent release of many apoptotic agents. According to reports, the production of ROS within the mitochondria results in damage to the mitochondrial membrane, depolarization of the Δψm, delivery of apoptogenic factors, and a reduction in the capacity for oxidative phosphorylation.Fig. 12 Mitochondrial membrane potential by Rhodamine 123 staining images A549 and H1299 cells with the AO-EB staining after treatment with free SF, BA@SF@ZIF/DA/DL, and BA@SF@ZIF/KM/DA/DL. Scale bar 100 μm.

Fig. 12

Fig. 12 shows the MMP of A549 and H1299 cells treated with IC50 concentration of SF, BA@SF@ZIF/DA/GL, and BA@SF@ZIF/KM/DA/GL. The control cells exhibit enhanced green fluorescence, which indicates increased MMP, as displayed in Fig. 12. As an illustration of the decreased MMP status, the A549 and H1299 cells treated with IC50 concentration of SF, BA@SF@ZIF/DA/GL, and BA@SF@ZIF/KM/DA/GL showed reduced/dull green fluorescence. Thus, it was evident that the prepared SF could suppress the MMP in the A549 and H1299 cells, BA@SF@ZIF/DA/GL, and BA@SF@ZIF/KM/DA/GL combination.

3.10 BA@SF@ZIF/KM/DA/GL improved the ROS level

The breakdown and incomplete decomposition of oxygen molecules, damage to cell components, and oxygen intake for cell survival generate reactive oxygen species. Increased ROS causes apoptosis by focusing on different signalling pathways, and it also controls the various physiological and pathological states in cancer by raising the ROS level in the mitochondria. Using the DCFH-DA staining technique, the effect of BA@SF@ZIF/DA/GL and BA@SF@ZIF/KM/DA/GL on the formation of ROS in mitochondria was investigated in this work. The findings are shown in Fig. 13. A significant rise in ROS production was displayed when comparing BA@SF@ZIF/DA/GL and BA@SF@ZIF/KM/DA/GL-treated lung cancer cells to control cells. Increased fluorescence intensity was accompanied in the A549 and H520 cells treated with BA@SF@ZIF/DA/GL and BA@SF@ZIF/KM/DA/GL, indicating that the mitochondrial cells produce ROS. The elevated production of reactive oxygen species (ROS) within the mitochondria results in the suppression of the antioxidant system and the depolarization of the mitochondrial membrane potential (Δψm), both triggering programmed cell death.Fig. 13 ROS quantification by DCFH-DA staining images A549 and H1299 cells with free SF, BA@SF@ZIF/DA/DL, and BA@SF@ZIF/KM/DA/DL. Scale bar 100 μm.

Fig. 13

Using DCFH-DA staining, the intracellular ROS levels in the A549 and H1299 treated with IC50 concentration of SF, BA@SF@ZIF/DA/GL and BA@SF@ZIF/KM/DA/GL were measured. The results are shown in Fig. 13. The A549 and H1299 cells treated with IC50 concentration of SF, BA@SF@ZIF/DA/GL and BA@SF@ZIF/KM/DA/GL showed bright green fluorescence that showed improved ROS status, whereas the control cells showed very little green fluorescence, which indicates the trace level of ROS. This result shows that adding fabricated SF, BA@SF@ZIF/DA/GL, and BA@SF@ZIF/KM/DA/GL to the A549 and H1299 cells raised their ROS level.

3.11 BA@SF@ZIF/KM/DA/GL improved the caspases activity

Most chemotherapy drugs cause apoptosis in tumour cells; nevertheless, tumour cells may also evade apoptosis, which may be related to the emergence of chemotherapeutic agent resistance. Apoptosis is mainly initiated by signals from two distinct cascades: the extrinsic and intrinsic routes, which are triggered by caspase-8 and caspase-9. According to the results of this study, the A549 and H1299 cells had apoptotic cell death treated with IC50 concentration of SF, BA@SF@ZIF/DA/GL and BA@SF@ZIF/KM/DA/GL, improving the caspase-3, caspase-8, and caspase-9 activities. Involved in many essential biochemical and physiological processes are mitochondria. Cell signalling, apoptosis control, and energy metabolism all depend on mitochondria. Changes in the mitochondria, such as the collapse of the membrane potential, may cause cytochrome c to leak into the cytosol, which in turn may activate caspases and induce apoptosis. We also showed reduced MMP levels in the A549 and H1299 treated with SF, BA@SF@ZIF/DA/GL, and BA@SF@ZIF/KM/DA/GL.

Assay kits were used to assess the caspase-3, caspase-8, and caspase-9 activities in the control and SF, BA@SF@ZIF/DA/GL and BA@SF@ZIF/KM/DA/GL treated A549 and H1299 cells. The results are shown in Fig. 14. As shown in Fig. 14, caspase activities were expected in the control cells. In contrast, A549 and H1299 cells were IC50 concentrations of SF, BA@SF@ZIF/DA/GL, and BA@SF@ZIF/KM/DA/GL. This result shows that treating SF, BA@SF@ZIF/DA/GL, and BA@SF@ZIF/KM/DA/GL could increase caspase activity and cause apoptosis in the A549 and H1299 cells.Fig. 14 Effects of free SF, BA@SF@ZIF/DA/DL, and BA@SF@ZIF/KM/DA/DL on caspase-3, -8, -9 in 143B cells by the ELISA assay for 24 h. Bars represent the mean ± standard deviation of individual experiments performed in triplicate. GraphPad Prism 8.0 was used to evaluate statistical significance. P-values <0.001 were considered statistically significant diﬀerence and marked with ***, respectively.

Fig. 14

4 Conclusions

In conclusion, SF or KM@ZIF-8 were synthesised and characterized, then complexed with Au3+ ions and conjugated with GL to provide a targeted drug delivery system. A series of characterizations confirmed the construction of BA@SF@ZIF/DA/GL and BA@SF@ZIF/KM/DA/GL. Over the days, pH-sensitive drug delivery devices released the SF and KM encapsulated form. It was also shown that BA@SF@ZIF/DA/GL was more effective in A549 and H1299 cells than BA@SF@ZIF/KM/DA/GL. Apoptotic cell death was observed in A549 and H1299 cells treated with SF-loaded pH-responsive drug delivery devices. The fabricated BA@SF@ZIF/DA/GL and BA@SF@ZIF/KM/DA/GL are promising candidates for therapeutic chemotherapy agents.

Funding

Not applicable.

Ethics declarations

Not applicable.

Data availability

All data generated or analyzed during this research are included in this published article.

CRediT authorship contribution statement

Chenggang Lei: Writing – original draft, Methodology, Formal analysis. Di Liu: Writing – original draft, Methodology, Formal analysis. Qian Zhou: Writing – original draft, Investigation, Data curation. Shengwei Ma: Validation, Methodology, Data curation. Haiyun Qian: Writing – review & editing, Project administration, Conceptualization.

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.

Acknowledgements

Not applicable.
==== Refs
References

1 Leiter A. Veluswamy R.R. Wisnivesky J.P. The global burden of lung cancer: current status and future trends Nat. Rev. Clin. Oncol. 2023 1 16
2 Chen Q. Jiao D. Wu Y. Wang L. Hu H. Song J. Yan J. Wu L. Functional and pathway enrichment analysis for integrated regulatory network of high- and low-metastatic lung cancer Mol. Biosyst. 9 2013 3080 3090 10.1039/C3MB70288J 24077187
3 Doroudian M. MacLoughlin R. Poynton F. Prina-Mello A. Donnelly S.C. Nanotechnology based therapeutics for lung disease Thorax 74 2019 10.1136/thoraxjnl-2019-213037 965 LP – 976
4 Wang Y. Li Q. Deng M. Chen K. Wang J. Self-assembled metal-organic frameworks nanocrystals synthesis and application for plumbagin drug delivery in acute lung injury therapy Chinese Chem. Lett. 33 2022 324 327
5 Zhu H. Liu H. Zhu J.-H. Wang S.-Y. Zhou S.-S. Kong M. Mao Q. Long F. Fang Z.-J. Li S.-L. Efficacy of ginseng and its ingredients as adjuvants to chemotherapy in non-small cell lung cancer Food Funct. 12 2021 2225 2241 10.1039/D0FO03341C 33595586
6 Kim H. Goh S.-H. Choi Y. Quenched cetuximab conjugate for fast fluorescence imaging of EGFR-positive lung cancers Biomater. Sci. 2020 10.1039/D0BM01148G
7 Hoy H. Lynch T. Beck M. Surgical treatment of lung cancer Crit. Care Nurs. Clin. 31 2019 303 313
8 Zhang J. Hu J. Chan H.F. Skibba M. Liang G. Chen M. iRGD decorated lipid-polymer hybrid nanoparticles for targeted co-delivery of doxorubicin and sorafenib to enhance anti-hepatocellular carcinoma efficacy Nanomedicine Nanotechnology, Biol. Med. 12 2016 1303 1311 10.1016/j.nano.2016.01.017
9 Shen Y.-C. Ou D.-L. Hsu C. Lin K.-L. Chang C.-Y. Lin C.-Y. Liu S.-H. Cheng A.-L. Activating oxidative phosphorylation by a pyruvate dehydrogenase kinase inhibitor overcomes sorafenib resistance of hepatocellular carcinoma Br. J. Cancer 108 2012 72 10.1038/bjc.2012.559 23257894
10 d'Avanzo N. Torrieri G. Figueiredo P. Celia C. Paolino D. Correia A. Moslova K. Teesalu T. Fresta M. Santos H.A. LinTT1 peptide-functionalized liposomes for targeted breast cancer therapy Int. J. Pharm. 597 2021 120346 10.1016/j.ijpharm.2021.120346
11 Lu J. Wang J. Ling D. Surface Engineering of nanoparticles for targeted delivery to hepatocellular carcinoma Small 14 2018 1702037 10.1002/smll.201702037
12 Li B.T. Smit E.F. Goto Y. Nakagawa K. Udagawa H. Mazières J. Nagasaka M. Bazhenova L. Saltos A.N. Felip E. Trastuzumab deruxtecan in HER2-mutant non–small-cell lung cancer N. Engl. J. Med. 386 2022 241 251 34534430
13 Schwartz A.D. Barney L.E. Jansen L.E. V Nguyen T. Hall C.L. Meyer A.S. Peyton S.R. A biomaterial screening approach reveals microenvironmental mechanisms of drug resistance Integr. Biol. 9 2017 912 924 10.1039/C7IB00128B
14 Hu Y. Yu D. Zhang X. 9-amino acid cyclic peptide-decorated sorafenib polymeric nanoparticles for the efficient in vitro nursing care analysis of hepatocellular carcinoma Process Biochem 100 2021 140 148 10.1016/j.procbio.2020.09.021
15 Zanzer Y.C. Plaza M. Dougkas A. Turner C. Östman E. Black pepper-based beverage induced appetite-suppressing effects without altering postprandial glycaemia, gut and thyroid hormones or gastrointestinal well-being: a randomized crossover study in healthy subjects Food Funct. 9 2018 2774 2786 10.1039/C7FO01715D 29691526
16 Ni K. Guo J. Bu B. Pan Y. Li J. Liu L. Luo M. Deng L. Naringin as a plant-derived bitter tastant promotes proliferation of cultured human airway epithelial cells via activation of TAS2R signaling Phytomedicine 84 2021 153491 10.1016/j.phymed.2021.153491
17 Younas M. Hano C. Giglioli-Guivarc’h N. Abbasi B.H. Mechanistic evaluation of phytochemicals in breast cancer remedy: current understanding and future perspectives RSC Adv. 8 2018 29714 29744 10.1039/C8RA04879G 35547279
18 Hajiashrafi S. Motakef Kazemi N. Preparation and evaluation of ZnO nanoparticles by thermal decomposition of MOF-5 Heliyon 5 2019 e02152 10.1016/j.heliyon.2019.e02152
19 Wu M. Yang Y. Metal–organic framework (MOF)‐based drug/cargo delivery and cancer therapy Adv. Mater. 29 2017 1606134
20 Saeb M.R. Rabiee N. Mozafari M. Verpoort F. Voskressensky L.G. Luque R. Metal–organic frameworks (MOFs) for cancer therapy Materials 14 2021 7277 34885431
21 Mazloom-Jalali A. Shariatinia Z. Tamai I.A. Pakzad S.-R. Malakootikhah J. Fabrication of chitosan–polyethylene glycol nanocomposite films containing ZIF-8 nanoparticles for application as wound dressing materials Int. J. Biol. Macromol. 153 2020 421 432 32151721
22 Taheri M. Ashok D. Sen T. Enge T.G. Verma N.K. Tricoli A. Lowe A. Nisbet D.R. Tsuzuki T. Stability of ZIF-8 nanopowders in bacterial culture media and its implication for antibacterial properties Chem. Eng. J. 413 2021 127511 10.1016/j.cej.2020.127511
23 Abdelhamid H.N. Zeolitic imidazolate frameworks (ZIF-8) for biomedical applications: a review Curr. Med. Chem. 28 2021 7023 7075 34102965
24 El-Aziz A. Ebrahem N.E. Abdelhamid H.N. A comparative study of the toxic effect of ZIF-8 and ZIF-L on the colonization and decomposition of shaded outdoor mice carrions by arthropods Sci. Rep. 12 2022 1 10 34992227
25 Kamal N.A.M.A. Abdulmalek E. Fakurazi S. Cordova K.E. Abdul Rahman M.B. Dissolution and biological assessment of cancer-targeting nano-zif-8 in zebrafish embryos ACS Biomater. Sci. Eng. 8 2022 2445 2454 35583465
26 Xu M. Hu Y. Ding W. Li F. Lin J. Wu M. Wu J. Wen L.-P. Qiu B. Wei P.-F. Rationally designed rapamycin-encapsulated ZIF-8 nanosystem for overcoming chemotherapy resistance Biomaterials 258 2020 120308
27 Shao X. Zhang X. Hu J. Gao T. Chen J. Xu C. Wei C. Dopamine 1 receptor activation protects mouse diabetic podocytes injury via regulating the PKA/NOX-5/p38áMAPK axis Exp. Cell Res. 388 2020 111849
28 de Donato A. Buonincontri V. Borriello G. Martinelli G. Mone P. The dopamine system: insights between kidney and brain, Kidney Blood Press Res. 47 2022 493 505
29 Wu L. Zheng T. Guan W. Han Q. Su H. Wu N. Zhang L. Li G. Anisotropic chitosan micropatterning containing metformin functionalized calcium titanate (CaTiO3) nanoparticles for regulating dorsal root ganglion behavior Surface. Interfac. 35 2022 102414 10.1016/j.surfin.2022.102414
30 Zhang S. Hou J. Yuan Q. Xin P. Cheng H. Gu Z. Wu J. Arginine derivatives assist dopamine-hyaluronic acid hybrid hydrogels to have enhanced antioxidant activity for wound healing Chem. Eng. J. 392 2020 123775
31 Steeves A.J. Atwal A. Schock S.C. Variola F. Evaluation of the direct effects of poly(dopamine) on the in vitro response of human osteoblastic cells J. Mater. Chem. B 4 2016 3145 3156 10.1039/C5TB02510A 32263052
32 Maruthapandi M. Natan M. Jacobi G. Banin E. Luong J.H.T. Gedanken A. Antibacterial activity against rethicillin-cesistant Staphylococcus aureus of dolloidal polydopamine prepared by carbon sot ntimulated polymerization of dopamine, Nanomater (Basel, Switzerland) 9 2019 10.3390/nano9121731
33 De D. Upadhyay P. Das A. Ghosh A. Adhikary A. Goswami M.M. Studies on cancer cell death through delivery of dopamine as anticancer drug by a newly functionalized cobalt ferrite nanocarrier Colloids Surfaces A Physicochem. Eng. Asp. 627 2021 127202
34 Lee S.Y. Shrestha S. Shrestha B.K. Park C.H. Kim C.S. Covalent surface functionalization of bovine serum albumin to ragnesium surface to provide cobust oorrosion inhibition and enhance in vitro isteo-snductivity Polymers 12 2020 10.3390/polym12020439
35 Huang P. Kong Y. Li Z. Gao F. Cui D. Copper nelenide aanosnakes: bovine serum albumin-rssisted coom temperature kontrollable synthesis and characterization Nanoscale Res. Lett. 5 2010 949 10.1007/s11671-010-9587-0 20672034
36 Brown G.M. Huckerby T.N. Morris H.G. Abram B.L. Nieduszynski I.A. Oligosaccharides derived from bovine articular cartilage seratan kulfates after deratanase II iigestion: kmplications for feratan sulfate structural Fingerprinting Biochemistry 33 1994 4836 4846 10.1021/bi00182a012 8161543
37 Wu J.J. Eyre D.R. Identification of hydroxypyridinium crosslinking sites in type II collagen of bovine articular cartilage Biochemistry 23 1984 1850 1857 10.1021/bi00303a041 6426508
38 Strawich E. Nimni M.E. Properties of a collagen molecule containing three identical components extracted from bovine articular cartilage Biochemistry 10 1971 3905 3911 10.1021/bi00797a017 4334282
39 Garza-Ocañas L. Ferrer D.A. Burt J. Diaz-Torres L.A. Ramírez Cabrera M. Rodríguez V.T. Luján Rangel R. Romanovicz D. Jose-Yacaman M. Biodistribution and long-term fate of silver nanoparticles functionalized with bovine serum albumin in rats Metallomics 2 2010 204 210 21069158
40 Mukhopadhyay S. Gupta R.K. Paitandi R.P. Rana N.K. Sharma G. Koch B. Rana L.K. Hundal M.S. Pandey D.S. Synthesis, structure, DNA/hrotein binding, and anticancer activity of some salf-candwich Cyclometalated Rh(III) and Ir(III) complexes Organometallics 34 2015 4491 4506 10.1021/acs.organomet.5b00475
41 Wydooghe E. Vandaele L. Beek J. Favoreel H. Heindryckx B. De Sutter P. Van Soom A. Differential apoptotic staining of mammalian blastocysts based on double immunofluorescent CDX2 and active caspase-3 staining Anal. Biochem. 416 2011 228 230 10.1016/j.ab.2011.05.033 21684250
42 Wang B. Hu W. Yan H. Chen G. Zhang Y. Mao J. Wang L. Lung cancer chemotherapy using nanoparticles: enhanced target ability of redox-responsive and pH-sensitive cisplatin prodrug and paclitaxel Biomed. Pharmacother. 136 2021 111249 10.1016/j.biopha.2021.111249
43 Subarkhan M.K.M. Ramesh R. Ruthenium(ii) arene complexes containing benzhydrazone ligands: synthesis, structure and antiproliferative activity Inorg. Chem. Front. 3 2016 1245 1255 10.1039/C6QI00197A
44 Giriraj K. Mohamed Kasim M.S. Balasubramaniam K. Thangavel S.K. Venkatesan J. Suresh S. Shanmugam P. Karri C. Various coordination modes of new coumarin Schiff bases toward Cobalt (III) ion: synthesis, spectral characterization, in vitro cytotoxic activity, and investigation of apoptosis Appl. Organomet. Chem. 36 2022 e6536 10.1002/aoc.6536
45 Mohan N. Mohamed Subarkhan M.K. Ramesh R. Synthesis, antiproliferative activity and apoptosis-promoting effects of arene ruthenium(II) complexes with N, O chelating ligands J. Organomet. Chem. 859 2018 10.1016/j.jorganchem.2018.01.022
46 Mohamed Kasim M.S. Sundar S. Rengan R. Synthesis and structure of new binuclear ruthenium(II) arene benzil bis(benzoylhydrazone) complexes: investigation on antiproliferative activity and apoptosis induction Inorg. Chem. Front. 5 2018 585 596 10.1039/c7qi00761b
47 Balaji S. Mohamed Subarkhan M.K. Ramesh R. Wang H. Semeril D. Synthesis and structure of arene Ru(II) N∧O-chelating complexes: in vitro cytotoxicity and cancer cell death mechanism Organometallics 39 2020 1366 1375 10.1021/acs.organomet.0c00092
48 Wang Y. Jin J. Shu L. Li T. Lu S. Subarkhan M.K.M. Chen C. Wang H. New srganometallic ruthenium(II) compounds aynergistically show cytotoxic, antimetastatic and Antiangiogenic activities for the treatment of metastatic cancer Chem. Eur J. 26 2020 15170 15182 10.1002/chem.202002970 32639591
49 Mohamed Subarkhan M.K. Ren L. Xie B. Chen C. Wang Y. Wang H. Novel tetranuclear ruthenium(II) arene complexes showing potent cytotoxic and antimetastatic activity as well as low toxicity in vivo Eur. J. Med. Chem. 179 2019 10.1016/j.ejmech.2019.06.061
50 Kalaiarasi G. Mohamed Subarkhan M. Fathima Safwana C.K. Sruthi S. Sathiya Kamatchi T. Keerthana B. Ashok Kumar S.L. New organoruthenium(II) complexes containing N, X-donor (X = O, S) heterocyclic chelators: synthesis, spectral characterization, in vitro cytotoxicity and apoptosis investigation Inorganica Chim. Acta. 535 2022 120863 10.1016/j.ica.2022.120863
51 Pilliadugula R. Haribabu J. Mohamed Subarkhan M.K. Echeverria C. Karvembu R. Gopalakrishnan N. Effect of morphology and (Sn, Cr) doping on in vitro antiproliferation properties of hydrothermally synthesized 1D GaOOH nanostructures J. Sci. Adv. Mater. Devices. 6 2021 351 363 10.1016/j.jsamd.2021.03.003
52 Swaminathan S. Haribabu J. Mohamed Subarkhan M.K. Gayathri D. Balakrishnan N. Bhuvanesh N. Echeverria C. Karvembu R. Impact of aliphatic acyl and aromatic thioamide substituents on the anticancer activity of Ru(ii)-p-cymene complexes with acylthiourea ligands—in vitro and in vivo studies Dalt. Trans. 50 2021 16311 16325 10.1039/D1DT02611A
53 Mohamed Subarkhan M.K. Ramesh R. Liu Y. Synthesis and molecular structure of arene ruthenium(II) benzhydrazone complexes: fmpact of substitution at the chelating ligand and arene moiety on antiproliferative activity New J. Chem. 40 2016 10.1039/c6nj01936f
54 Dorairaj D.P. Haribabu J. Dharmasivam M. Malekshah R.E. Mohamed Subarkhan M.K. Echeverria C. Karvembu R. Ru(II)-p-Cymene complexes of Furoylthiourea ligands for anticancer applications against breast cancer cells Inorg. Chem. 62 2023 11761 11774 10.1021/acs.inorgchem.3c00757 37459067
55 Sathiya Kamatchi T. Mohamed Subarkhan M.K. Ramesh R. Wang H. Małecki J.G. Investigation into antiproliferative activity and apoptosis mechanism of new arene Ru(ii) carbazole-based hydrazone complexes Dalt. Trans. 49 2020 11385 11395 10.1039/D0DT01476A
56 Swaminathan S. Haribabu J. Mohamed Subarkhan M.K. Manonmani G. Senthilkumar K. Balakrishnan N. Bhuvanesh N. Echeverria C. Karvembu R. Coordination behavior of acylthiourea ligands in their Ru(II)–Benzene Complexes─Structures and anticancer activity Organometallics 41 2022 1621 1630 10.1021/acs.organomet.2c00127
57 Liu K. Liu P. Liu R. Wu X. Dual AO/EB staining to detect apoptosis in osteosarcoma cells compared with flow cytometry Med. Sci. Monit. Basic Res. 21 2015 15 20 10.12659/MSMBR.893327 25664686
58 Kazimirova A. Baranokova M. Staruchova M. Drlickova M. Volkovova K. Dusinska M. Titanium dioxide nanoparticles tested for genotoxicity with the comet and micronucleus assays in vitro, ex vivo and in vivo Mutat. Res. Toxicol. Environ. Mutagen 2019 10.1016/j.mrgentox.2019.05.001
59 Bargathulla I. Aadhil Ashwaq B. Sathiyaraj S. Sultan Nasar A. ElangovanVellaichamy, Pegylated bis-indolyl polyurethane dendrimer: Empty drug carrier with prominent anticancer activity Eur. Polym. J. 153 2021 110491 10.1016/j.eurpolymj.2021.110491
