Fundamental Research On The Preparation Of Pingyangmycin-albumin Microspheres And The Application For The Treatment Of The Vascular Malformations In Oral And Maxillofacial Region

Hemangioma and vascular malformation are the most common diseases among infants and young kids, and vascular malformation also can be observed in adults. In addition, these diseases are most frequently occurred in oral and maxillofacial region, which are about 60% of whole body. Because these diseases occurred in the oral and maxillofacial region, they cause facial malformation and dysfunction together with infection and bleeding. They are serious diseases that influence patient both physically and psychologically as well as daily life.For the treatment of hemangioma and vascular malformation, one of the most common methods is injection of drugs into the tumors and malformations. This has been widely used in clinic since the report of using Bleomycin for successfully treating lymphangiomas in 1977. Pingyangmycin(PYM) is a domestic manufactured antitumor drug, which has the same structure of Bleomycin A₅(i.e., Bleomycin A5). The research has shown that it has minor side effects but without damaging the blood and immunity systems. There are enormous reports in this country that very satisfactory treatments of hemangiomas and vascular malformations usingintralesional injection of PYM have been achieved.Based on clinical observations, the method of intralesional injection of PYM is good for treating hemangiomas and vascular malformations, but when it is for treating big venous malformations, it takes longer cycle and not good for arteriovenous malformations. This project is aimed to reduce the cycle, toxicities and the costs of patients. Albumin microspheres will be used as a carrier, and Pingyangmycin-albumin microspheres(PYM-AMS) will be prepared and investigated.In this research, the PYM-AMS with average particles of 139.22 um are prepared at 140°C by the method of comparison analysis. The loading rate of drug is up to 26.47%. The drug is sustained-releasing and about 88% is released in 24 hours. The PYM-AMS is screened and packed. It has been shown that the prepared PYM-AMS has no toxic and side effects in the acute toxicity and safety experiments of Japanese big ear rabbits.In the experiment of inhibiting the growth of the cells of the human endothelial cell line(ECV304), the prepared PYM-AMS has shown similar results as the PYM injection agent, showing a dose- and time-dependent inhibitory effect, but the blank protein particles have no effects.For animal tests, the ear central arteries of Japanese big ear rabbit are selected as the experimental model. The PYM-AMS is administered by being mixed with soybean oil, and it is compared with PYM injection agent that is clinical used now. These drugs were infused respectively in the ear central arteries of 24 Japanese big ear rabbits. The influences on endothelia and arteries are examined. The results suggest that the PYM-AMS has thefollowing advantages, such as, making the endothelia and arteries defective, inducing proliferation of endothelial cells and smooth muscle cells after 14 days, causing the arteries sclerostenosis after 21 days, and its activities are stronger than the injection agent because that PYM-AMS have sustained-releasing drug and arterial embolization. This research has provided the laboratory evidences for the clinical treatment of hemangiomas and vascular malformations using the PYM-AMS.In summary, this project has developed a method to prepare the PYM-AMS with high drug loading rate and a pre-clinical treatment protocol of its application in the treatment of hemangiomas and vascular malformations. In addition, the possible mechanism of PYM acts on arteriovenous malformation has also been systematically explored, and the role of myofibroblast in the blood vessel sclerostenosis that is caused by PYM has been proposed first time.