The use of lipid-coated nanodiamond to improve bioavailability and efficacy of sorafenib in resisting metastasis of gastric cancer
Introduction
The metastasis is responsible for over 90% of cancer-associated mortality and remains one of the greatest challenges for successful cancer treatment [1]. Metastasis is the spread of cancer cells from primary tumor to lymph or blood vessels, and then colonized at distant tissues. Once the malignant cancer cells have metastasized to distant organs, it became largely incurable and fatal [2], [3]. Gastric cancer is the fourth most common cancer diagnosis worldwide and the second leading cause of cancer related-death in eastern Asia [4], [5], [6]. Moreover, gastric cancer tends to spread to lymph nodes and distant organs of liver, lung and kidney [7], [8], [9]. Metastasis has already occurred in 80–90% of patients diagnosed with gastric cancer, and the 5-year survival rate is less than 10% in these patients. Thereby, it is a great challenge to find an effective strategy for treatment of metastatic cancer and improvement of survival benefits, which significantly depends on the capacity to interdict the process of cancer metastasis to distant organs.
Angiogenesis, the process of new blood vessel formation, plays a crucial role in tumor growth and cancer metastasis [3], [10], [11]. Importantly, angiogenesis is an essential component of cancer metastasis and critically required in certain aspects of cancer metastasis, such as intravasation, extravasation and establishment of metastatic foci in distant site. These new blood vessels can provide an efficient route for cancer cells to leave the primary site and enter the bloodstream, and support the growth of metastatic cells to form secondary tumors in distant tissues. Therein, vascular endothelial growth factor (VEGF), a general activator of endothelial cell proliferation and mobility, is especially important in the simulation of tumor angiogenesis [7], [8], [10]. Accordingly, inhibition of angiogenesis with VEGF inhibitors can be an important and effective strategy for the treatment of cancer metastasis. Sorafenib, an oral molecular-targeting agent with efficient anti-proliferative and antiangiogenic activities by blocking Raf signaling and VEGF, is potential for treatment of metastatic gastric cancer [12], [13], [14], [15], [16], [17]. However, sorafenib is almost insoluble in water or buffered solution at various pH values (from pH 1.2 to pH 7.4), and the oral bioavailability is extremely low (about 8.43%), which greatly restricts its therapeutic efficacy on cancer metastasis.
Nanodiamond (ND), a new member of carbon nanoparticle family, is emerging as a promising nanomaterial for various biomedical applications [18], [19], [20]. ND has superior physical and chemical properties of versatile functionalization, large surface area, high adsorption capacity and good biocompatibility, which makes it attractive for drug delivery and cellular imaging [19], [21], [22], [23]. ND can spontaneously form nanometer-sized clusters in aqueous solution, which could facilitate the loading of therapeutic agents on the surface or in the internal nano-scaled pores of ND clusters by non-covalent interactions [18], [19]. To date, a few therapeutic agents including small molecules, proteins and nucleic acids has been investigated and efficiently delivered with enhanced therapeutic efficacy [24], [25], [26], [27], [28], [29]. However, the application of ND as a new drug carrier for cancer therapy is still in its infancy. Up to now, the in vivo behavior of ND after oral administration still remains unclear. Moreover, almost no approaches of ND have been exploited as oral drug delivery platform for treatment of cancer metastasis.
Herein, we report on a lipid-coated nanodiamond loading water-insoluble sorafenib to enhance the oral bioavailability and efficacy on resisting the metastasis of gastric cancer to distant organs. The lipophilic sorafenib was loaded into ND clusters by physical adsorption, and then coated with an amphiphilic lipid of distearoylphosphatidylethanolamine-poly(ethylene glycol) (DSPE-PEG) (SND) to improve the oral delivery and suppress the metastasis of gastric cancer.
Section snippets
Materials
Nanodiamond (ND) was provided by Nanjing XFNANO Materials Tech Co. Ltd (Jiangsu, China). Distearoylphosphatidylethanolamine-poly (ethylene glycol) 2000 (DSPE-PEG) was purchased from Shanghai Advanced Vehicle Technology Pharmaceuticals Ltd (Shanghai, China). Sorafenib tosylate was obtained from Shengxin pharmaceuticals Ltd (Zhejiang, China). Hematoxylin and eosin (H&E) staining kit and 4′,6-diamidino-2-phenylindole (DAPI) provided by Beyotime Institute of Biotechnology (Zhejiang, China).
Characterization of SND
SND was prepared and the physicochemical properties of SND were characterized. ND usually spontaneously formed clusters of tens to hundreds nanometers in aqueous solution, even when it was dispersed by strong ultrasonication. Previous reports have demonstrated the carrier capabilities of ND with chemotherapeutic agents by direct physical adsorption [25], [26]. In this work, the water-insoluble sorafenib was firstly adsorbed on the surface or in the internal pores of ND clusters (ND + Sora) by
Conclusion
A lipid-coated nanodiamond drug delivery platform for improving the oral bioavailability of water-insoluble sorafenib (SND) and treatment of cancer metastasis was developed. SND were homogenous nanoassemblies with the mean diameter of 127.6 ± 12.9 nm. Compared with the drug suspension, the drug concentration in gastrointestinal tract and major organs was obviously increased by SND. Typically, the sorafenib concentration in primary tumor tissue was markedly improved 14.95 folds by SND. In tumor
Acknowledgments
The National Basic Research Program of China (2013CB932503, 2013CB932704 and 2012CB932502), the National Natural Science Foundation of China (81270047, 81373359) and Shanghai Program (12nm0501300) are gratefully acknowledged for financial support.
References (42)
- et al.
Quantum-dots based simultaneous detection of multiple biomarkers of tumor stromal features to predict clinical outcomes in gastric cancer
Biomaterials
(2012) - et al.
Basic and therapeutic aspects of angiogenesis
Cell
(2011) - et al.
Clinical pharmacokinetics of tyrosine kinase inhibitors
Cancer Treat Rev
(2009) - et al.
Mechanical properties and biomineralization of multifunctional nanodiamond-PLLA composites for bone tissue engineering
Biomaterials
(2012) - et al.
The long-term stability and biocompatibility of fluorescent nanodiamond as an in vivo contrast agent
Biomaterials
(2012) - et al.
Fluorescent nanodiamond as a probe for the intercellular transport of proteins in vivo
Biomaterials
(2013) - et al.
Nanodiamonds as intracellular transporters of chemotherapeutic drug
Biomaterials
(2010) - et al.
Nanodiamond-insulin complexes as pH-dependent protein delivery vehicles
Biomaterials
(2009) - et al.
Nanodiamonds-mediated doxorubicin nuclear delivery to inhibit lung metastasis of breast cancer
Biomaterials
(2013) - et al.
Oral drug delivery with polymeric nanoparticles: the gastrointestinal mucus barriers
Adv Drug Deliv Rev
(2012)
Endocytic carboxylated nanodiamond for the labeling and tracking of cell division and differentiation in cancer and stem cells
Biomaterials
A self-assembled nanocarrier loading teniposide improves the oral delivery and drug concentration in tumor
J Control Release
Nanoemulsion improves the oral absorption of candesartan cilexetil in rats: performance and mechanism
J Control Release
Solid lipid nanoparticles loading candesartan cilexetil enhance oral bioavailability: in vitro characteristics and absorption mechanism in rats
Nanomedicine NBM
In vivo biodistribution and toxicology of functionalized nano-graphene oxide in mice after oral and intraperitoneal administration
Biomaterials
Treating metastatic cancer with nanotechnology
Nat Rev Cancer
Metastasis: from dissemination to organ-specific colonization
Nat Rev Cancer
Tumor metastasis: mechanistic insights and clinical challenges
Nat Med
Gastric cancer epidemiology and risk factors
J Surg Oncol
Global cancer statistics
CA Cancer J Clin
Carcinoma of the stomach: a review of epidemiology, pathogenesis, molecular genetics and chemoprevention
World J Gastrointest Oncol
Cited by (102)
Kiwi-derived extracellular vesicles for oral delivery of sorafenib
2023, European Journal of Pharmaceutical SciencesBentonite as a water-insoluble amorphous solid dispersion matrix for enhancing oral bioavailability of poorly water-soluble drugs
2023, Journal of Controlled ReleaseGalactose engineered nanocarriers: Hopes and hypes in cancer therapy
2023, European Polymer JournalTargeted chitosan nanoparticles embedded into graphene oxide functionalized with caffeic acid as a potential drug delivery system: New insight into cancer therapy
2022, International Journal of Biological MacromoleculesImproving oral bioavailability of water-insoluble idebenone with bioadhesive liposomes
2022, Journal of Drug Delivery Science and Technology
- 1
These authors contributed equally to this work.