Zoledronate combined metal-organic frameworks for bone-targeting and drugs deliveries

www.nature.com/scientificreports OPEN Zoledronate combined metal‑organic frameworks for bone‑targeting and drugs deliveries Yixiao Pan1,3, Jiahao Wang1,3, Zichao Jiang1,3, Qi Guo1,3, Zhen Zhang1,3, Jingyi Li1,3, Yihe Hu2,3* & Long Wang1,3,4,5* Medicine treatments for bone-related diseases such as osteoporosis, bone metastasis, osteomyelitis, and osteolysis are often limited by insufficient drug concentration at the lesion sites owing to the low perfusion of bone tissue. A carrier that can deliver multiple bone destruction site-targeting drugs is required to address this limitation. Here, we reported a novel bone-targeting nano-drug delivery platform formed by the integration of zoledronate (ZOL) and zeolitic imidazolate framework-8 (ZIF-8) nanoparticles. The ZOL mixed zeolitic imidazolate framework (ZZF) nanoparticles were synthesized in water at room temperature (25 °C), where many biomacromolecules could maintain their activity. This allowed the ZZF nanoparticles to adapt the encapsulation ability and pH response release property from ZIF-8 and the excellent bone targeting performance of ZOL simultaneously. Considering the ease of preparation and biomacromolecule-friendly drug delivery of this nano platform, it may be useful in treating bone-related diseases. Osteoporosis, bone tumor, bone infection, and periprosthetic osteolysis are complicated illnesses in orthopedics. For these diseases, a combination of factors leads to systemic or local high bone turnover, thereby accelerating bone resorption and consequently causing bone deconstruction and reduced bone strength1–3. Although certain drugs can target these pathological changes, owing to insufficient blood supply, they might be metabolized before reaching an effective concentration at the lesion areas. Therefore, an efficient drug delivery platform targeting the bone resorption area is highly desirable. The nanomedicine delivery platform has been the focal point of numerous recent biochemical research studies. Nanoparticles with metal-organic frameworks (MOFs) have received increasing attention as nanomedicine delivery platforms. Jarai et al. evaluated the UiO-66, a zirconium and terephthalic acid based MOF, as a novel platform which have promising drugs loading and pulmonary delivery capacities4. Zhuang et al. investigated the platelet membrane-coated MOF as a nanodelivery system loaded with siRNA can achieving gene silencing in vivo5. The variety of MOF provides new ideas for medicine treatments, and the most important features for bone tissue-related diseases should be remarkable biosafety, multiple-drug loading capacities, and high bone targeting efficiency. The targeting capacity of nanoparticles is increased by combining them with bone-targeted agents (BTA) such as a ptamers6,7, and antibodies8,9 and small m olecules10,11. Zoledronate (ZOL), also known as zoledronic acid, is the third generation of bisphosphonate approved for the treatment of osteoporosis and bone m etastases12, and exhibits promising bone targeting ability, particularly at the high bone turnover sites13. Our previous study showed that PLGA nanoparticles loaded with ZOL enhanced bone-targeting abilities14. Previous studies have explored many methods of incorporating ZOL into nanoparticles. Sun et al. reported that ZOL anchored onto the mesoporous silica nanoparticles can yield bone-targeting ability10, Qiao et al. reported that ZOL conjugated onto the mesoporous silica-coated upconversion nanoparticles can target the osteocytes to attenuate early breast cancer bone m etastasis15. However, the methods of binding ZOL to nanoparticles discussed in these studies are considerably limited because they require the use of organic solvents 1 Department of Orthopedics, Xiangya Hospital, Central South University, Changsha, China. 2Department of Orthopedics, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China. 3Hunan Engineering Research Center of Biomedical Metal and Ceramic Implants, Xiangya Hospital, Central South University, Changsha, China. 4National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China. 5Hunan Key Laboratary of Aging Biology, Xiangya Hospital, Central South University, Changsha, China. *email: ; Scientific Reports | (2022) 12:12290 | https://doi.org/10.1038/s41598-022-15941-w 1 Vol.:(0123456789) www.nature.com/scientificreports/ Figure 1.  (A) Schematic illustration of the construction of the Cargos@ZZF nanoparticles and PVP coating. Cargos represent different substances such as doxorubicin, bovine serum albumin, and siRNA. (B) Schematic illustration demonstrating the osteolysis area targeting ability of the ZZF@PVP nanoparticles in the calvaria resorption mouse model. such as DMF and DMSO and prolonged heating, which pose serious challenges for many biomacromolecules such as nucleic acids and proteins. Considering the aforementioned factors, we focused on a promising nanoparticle, Zeolitic imidazolate framework-8 (ZIF-8), which is a member of ZIFs and consists of zinc ions and 2-methyl-imidazole (2-MIM). ZIF-8 was frequently employed as a nanocarrier for many bio-macromolecules owing to its low toxicity and remarkable biocompatibility16–18. Moreover, ZIF-8 can be synthesized in water at room temperature (25 °C) thereby allowing biomedical macromolecules to retain their activities when loaded19–21. We noted both 2-MIM and ZOL have an imidazole group. Based on this, we suspected that ZOL could possibly play a role in the synthesis process of ZIF-8 and form novel mixed ZOL-ligands zeolite frame (ZZF) nanoparticles which could simultaneously adapt the excellent carrier properties of ZIF-8 and the remarkable bone-targeting ability of ZOL. Therefore, in this study, we constructed a bone-targeting drug delivery platform based on the ZIF-8 with mixed ZOL and 2-MIM ligands (ZZF) nanoparticles (Figure 1). We first investigated the various cargo loading abilities of the ZZF nanoparticles and their pH-sensitive release behaviors. The cellular internalization and toxicity were conducted in vitro, and the bone resorption area targeting the ability of ZZF was detected by fluorescence imaging using a mouse calvaria resorption model. This nanoplatform, which is easily synthesized, and exhibits biosafety and multiple-drug loading capacity bone-targeting features presents fascinating application prospects in bone resorption lesions. Results and discussion Synthesis and characterizations of ZZF@PVP nanoparticles. The morphology of the ZIF-8 and ZZF@PVP nanoparticles was characterized by a transmission electron microscope (TEM). The ZIF-8 nanoparticles synthesized in aqueous were spherical with certain faceted particles being approximately 80 nm in size, which is an indication of the initial stages of crystallization of the ZIF-8 nanoparticles22. Following the addition Scientific Reports | Vol:.(1234567890) (2022) 12:12290 | https://doi.org/10.10 (...truncated)