دانلود رایگان مقاله طراحی هیالورونیداز کایمریک برای تجویز زیر جلدی بیوفارماکیوتیکال

عنوان فارسی
طراحی و آماده سازی هیالورونیداز کایمریک به عنوان مراقبی برای تجویز زیر جلدی بیوفارماکیوتیکال
عنوان انگلیسی
Design and preparation of chimeric hyaluronidase as a chaperone for the subcutaneous administration of biopharmaceuticals
صفحات مقاله فارسی
0
صفحات مقاله انگلیسی
10
سال انتشار
2016
نشریه
الزویر - Elsevier
فرمت مقاله انگلیسی
PDF
کد محصول
E445
رشته های مرتبط با این مقاله
شیمی
گرایش های مرتبط با این مقاله
مهندسی فرایند و شیمی کاربردی
مجله
مجله مهندسی بیوشیمی - Biochemical Engineering Journal
دانشگاه
موسسه مهندسی فرآیند، دانشگاه علوم، پکن، روابط چین
کلمات کلیدی
DNA نوترکیب، فرهنگ رزرو دسته ای، تصفیه، پزشکی، اثر طولانی هیالورونیداز، تجویز زیر جلدی
۰.۰ (بدون امتیاز)
امتیاز دهید
چکیده

Abstract


Subcutaneous (SC) delivery of biomacromolecular pharmaceuticals such as proteins often encounter barriers in the extracellular matrix, especially the hyaluronan (HA) network. In this study, chimeric hyaluronidases were designed, prepared and tested for assisting biopharmaceuticals in ID administration in mice as replacement of SC administration. The chimeras were hyaluronidase (rhPH20) conjugated with human serum albumin (rhPH20-HSA) and antibody Fc fragment (rhPH20-Fc). Expression of the new protein was undertaken in CHO cells cultured in a 5-L disposable bioreactor. Purification was carried out by a series of chromatographic methods to obtain high-purity products of 61 kDa (rhPH20), 79 kDa (rhPH20-HSA) and 190 kDa (rhPH20-Fc). The chimeric proteins rhPH20-HSA and rhPH20-Fc performed fairly well as spreading factors in short-term trypan blue intradermal (ID) infusion in comparison with recombinant hyaluronidase (rhPH20). They extended the channel opening from 24 h (rhPH20) to 85–120 h in vivo. The specific activity of rhPH20-Fc was 35,600 U/mg, higher than that of rhPH20-HSA (10,000 U/mg). Co-administration of rhPH20-Fc with two biomacromolecular pharmaceuticals, Stelara (150 KDa) and TNFRII-Fc-IL1ra (TFI, 250 kDa), through an ID route increased the bioavailability from 86% to 93% and from 64% and 97%, respectively, compared with rhPH20. The pharmacokinetic profile of ID administrated larger TFI was significantly improved through cooperation with the long-acting hyaluronidase.

نتیجه گیری

4. Conclusions


The newly designed chimeric hyaluronidases, rhPH20-Fc and rhPH20-HSA, are better chaperones than previous rhPH20 for subcutaneous administration of biopharmaceuticals because of their ability to extend the opening time of channels in the extracellular matrix, thus facilitating large molecules to penetrate though. This has been demonstrated by the dermis reconstruction testing where rhPH20 only extended the opening time of ECM channels for 24 h, while rhPH20-HSA and rhPH20-Fc could reach 85–120 h. The specific activity of rhPH20-Fc is higher than that of rhPH20-HSA. The improvement by rhPH20-Fc as a chaperone for Stelara (150 kDa) was obvious but not significant over rhPH20. However, for TFI with molecular weight 250 kDa, PH20-Fc performed much better than rhPH20. Compared with injection alone, co-administration of the large biopharmaceuticals with rhPH20-Fc improved Tmax as well as Cmax. In addition, the pharmaceutical profiles were optimized in a gradual change mode. This study is a step forward in development of subcutaneous administration for the delivery of biomacromolecular pharmaceuticals.


بدون دیدگاه