Outline

  • Abstract
  • Introduction
  • Results
  • Discussion
  • Conclusion
  • Materials and Methods
  • References
  • Acknowledgements
  • Author Information
  • Rights and Permissions
  • About This Article

رئوس مطالب

  • چکیده
  • کلیدواژه ها
  • مقدمه
  • نتایج
  • اثر کلرید کلسیم و محلول انحلال ژل در فعالیت زیستی آدنوویروس
  • حفاظت طولانی مدت مقاومت آدنوویروس توسط ژل
  • بررسی اثربخشی ضد توموری DWP418 در بافت تومور
  • بحث
  • نتیجه گیری
  • مواد و روش ها
  • لاین ها و کشت سلولی
  • جذب سلولی آدنوویروس آزاد شده از ژل
  • تجزیه و تحلیل مرتب سازی سلول فعال شده توسط فلوئورسانس
  • سنجش MTT
  • خصوصیات رهاسازی پایدار آدنوویروس در داخل بدن
  • تجزیه و تحلیل بافت شناسی و ایمونوهیستوشیمی
  • ارزیابی پراکندگی زیستی آدنوویروس با Q-PCR بیدرنگ
  • تجزیه و تحلیل آماری

Abstract

Adenoviruses (Ad) have been investigated for their efficacy in reducing primary tumors after local intratumoral administration. Despite high Ad concentrations and repetitive administration, the therapeutic efficacy of Ad has been limited because of rapid dissemination of the Ad into the surrounding normal tissues and short maintenance of Ad biological activity in vivo. To maximize the therapeutic potential of Ad-mediated gene therapeutics, we investigated the efficacy of local, sustained Ad delivery, using an injectable alginate gel matrix system. The biological activity of Ad loaded in alginate gel was prolonged compared with naked Ad, as evidenced by the high green fluorescent protein gene transduction efficiency over an extended time period. Moreover, oncolytic Ad encapsulated in alginate gel elicited 1.9- to 2.4-fold greater antitumor activity than naked Ad in both C33A and U343 human tumor xenograft models. Histological and quantitative PCR analysis confirmed that the oncolytic Ad/alginate gel matrix system significantly increased preferential replication and dissemination of oncolytic Ad in a larger area of tumor tissue in vivo. Taken together, these results show that local sustained delivery of oncolytic Ad in alginate gel augments therapeutic effect through selective infection of tumor cells, sustained release and prolonged maintenance of Ad activity.

Keywords: - - -

Conclusions

We successfully combined biocompatible alginate gel and Ad to create a delivery system that maximized the full therapeutic potential of oncolytic Ad. The biological activity of Ad loaded in alginate gel was preserved for an extended period of time, as evidenced by the high GFP gene transduction efficiency over a prolonged time period compared with naked Ad. In addition, together with preserved biological activity, sustained release of oncolytic Ad from the locally administered alginate gel resulted in the continued delivery of Ad in tumor tissue, ultimately leading to enhanced antitumor therapeutic efficacy. To our knowledge, this is the first study to demonstrate the efficacy of a locally injectable delivery system for oncolytic Ad, demonstrating that the microenvironment in a matrix-based delivery system for Ad allows sustained Ad release and biological activity, thus enhancing the gene transduction efficacy as well as the antitumor therapeutic effect. The use of this Ad delivery system could help to maximize the therapeutic effects of oncolytic Ad.

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