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摘要 : 虽然存在宿主反应引起的并发症,且长期有效性仍有待确定,但人们对细菌生物疗法的兴趣仍然日益浓厚。

 虽然存在宿主反应引起的并发症,且长期有效性仍有待确定,但人们对细菌生物疗法的兴趣仍然日益浓厚。Omar Din及同事设计了群体感应时钟,并将其置入一个沙门氏菌菌株中,该菌株能释放一种肿瘤靶向毒素定位实体肿瘤。时钟驱动着菌落的周期性溶菌,以此在控制菌群数量的同时,确保抗肿瘤毒素在小鼠癌症模型中的持续施放。虽然这一系统在目前情况下仍然不是一种有效的疗法,但这项研究表明,合成生物学方法可被用于实现治疗剂在体内的持续动态输送。


Synchronized cycles of bacterial lysis for in vivodelivery


The widespread view of bacteria as strictly pathogenic has given way to an appreciation of the prevalence of some beneficial microbes within the human body1, 2, 3. It is perhaps inevitable that some bacteria would evolve to preferentially grow in environments that harbour disease and thus provide a natural platform for the development of engineered therapies4, 5, 6. Such therapies could benefit from bacteria that are programmed to limit bacterial growth while continually producing and releasing cytotoxic agents in situ7, 8, 9, 10. Here we engineer a clinically relevant bacterium to lyse synchronously at a threshold population density and to release genetically encoded cargo. Following quorum lysis, a small number of surviving bacteria reseed the growing population, thus leading to pulsatile delivery cycles. We used microfluidic devices to characterize the engineered lysis strain and we demonstrate its potential as a drug delivery platform via co-culture with human cancer cells in vitro. As a proof of principle, we tracked the bacterial population dynamics in ectopic syngeneic colorectal tumours in mice via a luminescent reporter. The lysis strain exhibits pulsatile population dynamics in vivo, with mean bacterial luminescence that remained two orders of magnitude lower than an unmodified strain. Finally, guided by previous findings that certain bacteria can enhance the efficacy of standard therapies11, we orally administered the lysis strain alone or in combination with a clinical chemotherapeutic to a syngeneic mouse transplantation model of hepatic colorectal metastases. We found that the combination of both circuit-engineered bacteria and chemotherapy leads to a notable reduction of tumour activity along with a marked survival benefit over either therapy alone. Our approach establishes a methodology for leveraging the tools of synthetic biology to exploit the natural propensity for certain bacteria to colonize disease sites.

来源: Nature 浏览次数:1


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