Bone-targeting Nano-drug Delivery System
Bone is an important part of the human body and is composed of periosteum, bone and bone marrow. Normal bones are always in the dynamic equilibrium of bone formation and bone resorption in bone reconstruction, and they coordinate with each other to maintain the physiological functions of bones. If the pathological change occurs during normal bone reconstruction, various bone diseases such as osteoporosis, deformity osteitis, bone metastases, primary and secondary bone tumors, and osteoarthritis will occur. Due to the high hardness, poor permeability, and special physiological and biochemical processes of the bone tissue, it is difficult for the general route of administration to transport the drug to the lesion site. Drugs often need to be administered systemically, increasing the dose to achieve an effective therapeutic concentration in bone tissue, which not only reduces the drug treatment index, but also causes severe toxic and side effects on patients’ non-bone tissues or organs. Osteotropic drug delivery system (ODDS) can specifically deliver drugs to bone tissues, thereby reducing their distribution and binding in non-bone tissues.
Drugs for the treatment of bone diseases are common with lipophilic compounds. Improving the solubility and bioavailability of bone-targeting drugs to achieve effective bone therapeutic concentrations is one of the scientific issues facing. Nanotechnology can change the physical and chemical properties of drugs (such as saturation solubility, dissolution rate, crystal form, and hydrophobic and hydrophilic properties of particle surfaces), and drug responsiveness (such as light, electricity, magnetic field responsiveness, pH sensitivity, and temperature sensitivity), and drug biological characteristics (such as specific molecular affinities), which affect the biological conversion (ADME), bioadhesion, in vivo stability, oral bioavailability, sustained and controlled release characteristics, targeting, long-circulation characteristics, bone marrow-blood barrier and other biopharmaceutical and pharmacokinetic behaviors, and ultimately achieve the purpose of enhancing drug efficacy, reducing adverse drug reactions, improving drug treatment index, enhancing formulation compliance, etc. The drug system has very important research value and practical significance for the treatment of clinical bone diseases.
- Physiological characteristics of bone
Bone tissue structure mainly includes outer bone matrix and inner bone marrow. There is a close vascular connection between the bone matrix and the inner bone marrow. When the drug is concentrated in the bone matrix, it naturally acts on the bone marrow and vice versa. Hydroxyapatite (HA) is the main component of adult bone matrix. The calcium that exists in the bone matrix in the form of HA accounts for about 99% of the total calcium in the human body, and the other 1% of calcium exists mostly in the amorphous form. Therefore, HA is an ideal specific binding site for bone targeted nano-delivery. Bone tissue contains special macrophages that allow particles and small cells in the blood circulation to enter the bone marrow. A particle size of less than 100 nm is a key factor in the passage of microparticles through the bone marrow-blood barrier. The average particle size of the bone-targeted nanometer drug delivery system is 10-100nm, which can smoothly reach the bone lesion site, thereby effectively improving the treatment effect and reducing toxic and side effects.
Lecithin, hydrogenated lecithin, and cholesterol were used to prepare cisplatin flexible nanoliposomes with an encapsulation rate of 88% and a particle size of 50-60 nm, which met the requirements for passive targeting of bone marrow. The nanoliposome mice tissue distribution experiment showed that the concentration of cisplatin in bone marrow is four times the concentration of free blood drug, the blood circulation time is prolonged, the drug clearance rate is reduced, and the tumor suppressive effect of cisplatin is improved.
Bone imaging is an important detection method for the bone disease treatment programs. The high specificity and high resolution of bone imaging are important in diagnosis. As a bone contrast agent, it must be highly specific to bone, stable in blood, able to avoid uptake by the reticuloendothelial system such as liver and spleen, low toxic and metabolizable. PEOPCL polymer was synthesized with polyoxyethylene (PEO) and polycaprolactone (PCL) under the catalysis of stannous octoate, and polymer micelles were loaded with bone diagnostic contrast agent. The critical micelle concentration of this polymer micelle is 25mg / L, and the particle size is 60nm. The polymer micelle bone development isotope 1251 has a labeling rate of 90%, a high bone uptake rate in the body, but a low liver and spleen uptake rate.
- Nanocomposite
Bone defects and bone non-union caused by trauma, infection, tumor and other reasons have always been difficult problems in the clinical rehabilitation process of orthopedics. The commonly used autologous and allogeneic bone transplantation methods have defects. Bone marrow mesenchymal stem cells (BMSCs) are derived from mesoderm and are found in connective tissues and interstitial organs of the body, with bone marrow being the most abundant. BMSCs are non-hematopoietic stem cells in the bone marrow, as well as hematopoietic structural and functional support cells in the bone marrow. They not only have mechanical support for bone marrow hematopoietic stem cells, but also secrete a variety of growth factors to promote hematopoietic function. BMSC has the advantages of easy sampling, strong regeneration ability, good osteogenesis ability, and weak immunogenicity. It has a variety of mesenchymal cell lineage differentiation in vitro and is easy for gene transfection. It is currently the first choice of seed cells in bone tissue engineering. Rat bone marrow mesenchymal stem cells and biomimetic nano-chitosan-collagen were cultured together to form a composite. The composite was implanted into the damaged bone of rats, and it was found that bone marrow mesenchymal thousand-cell nanocomposite could accelerate the formation of new bone, and the repair effect was significant with no immune rejection, which could be a new carrier for the treatment of bone defects.
Nanotechnology has changed the situation that bone-targeted drugs cannot pass the blood barrier of bone marrow, and the instantaneously high concentration of drugs is swallowed by the spleen or liver when intravenous drugs are administered, and improved the targeting efficiency and bioavailability of bone-targeted drugs, which has important scientific significance and application value for the treatment of bone diseases in the future.