New evidence suggests that the mechanism of nanoparticle entry into solid tumours may be driven by an active process. This insight paves the way for approaches to enhance the efficiency of nanomedicine delivery by harnessing active transport mechanisms, and encourage researchers to rethink how tumours are treated.
新證據表明納米顆粒可通過主動傳送途徑進入實體腫瘤，這為通過主動轉運機制提高納米藥物輸送效率奠定了基礎，同時鼓勵研究人員重新思考治療腫瘤的方法。The molecular and cellular mechanisms of nanoparticle delivery into solid tumours under in vivo physiological conditions have been a topic of considerable interest and controversy in the field of cancer nanomedicine. A commonly accepted mechanism for nanoparticle tumour delivery is based on the enhanced retention and permeability (EPR) effect, in which enhanced permeability arises from the leaky vasculature and fenestration of tumour blood vessels, and increased nanoparticle retention results from a collapse of the tumour lymphatic drainage system. However, recent data analysis reveals that perhaps less than 1% of the administrated nanoparticle dose could actually reach solid tumours in animal models. This low level of delivery efficiency, together with the disappointing clinical trials of nanotherapeutic drugs, has dampened the initial excitement for clinical translation.
In this context, the recent Article by Warren Chan and colleagues in Nature Materials is both timely and invigorating. This work demonstrates that an active delivery mechanism based on cellular transcytosis may be more dominant than passive EPR-based nanoparticle accumulation, thus creating new found optimism for in vivo nanoparticle delivery and tumour penetration. In xenograft tumour models, as well as several human tumour specimens, Chan and co-workers have found experimentally that there are simply not enough fenestrations or endothelial gaps on the wall of blood vessels to support efficient nanoparticle extravasation and accumulation. In comparison, active transcytosis by endothelial cells (involving active uptake, intracellular transport and exocytosis) appears to be far more efficient for in vivo nanoparticle delivery to solid tumours (Fig. 1a). However, much work is still needed to understand the detailed mechanisms as well as the structural factors that are important to active transcytosis. In this Comment, we first put active transcytosis and related concepts in perspective, then discuss new strategies for bypassing the bottlenecks of traditional nanoparticle delivery, and finally touch on the opportunities and challenges in translating nanoparticles for clinical oncology applications.
Active and passive mechanisms for in vivo nanoparticle delivery.
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