物理所合作設計細胞靶向策略 0

最新 07-19

【Abstract】

Cells can often be recognized by the concentrations of receptors expressed on their surface. For better (targeted drug treatment) or worse (targeted infection by pathogens), it is clearly important to be able to target cells selectively. A good targeting strategy would result in strong binding to cells with the desired receptor profile and barely binding to other cells. Using a simple model, we formulate optimal design rules for multivalent particles that allow them to distinguish target cells based on their receptor profile. We find the following: (i) It is not a good idea to aim for very strong binding between the individual ligands on the guest (delivery vehicle) and the receptors on the host (cell). Rather, one should exploit multivalency: High sensitivity to the receptor density on the host can be achieved by coating the guest with many ligands that bind only weakly to the receptors on the cell surface. (ii) The concentration profile of the ligands on the guest should closely match the composition of the cognate membrane receptors on the target surface. And (iii) irrespective of all details, the effective strength of the ligand–receptor interaction should be of the order of the thermal energy kBT, where T is the absolute temperature and kBis Boltzmann』s constant. We present simulations that support the theoretical predictions. We speculate that, using the above design rules, it should be possible to achieve targeted drug delivery with a greatly reduced incidence of side effects.

精準靶向細胞和組織是生物學研究中的一項重要挑戰。通常情況下，細胞可以通過在其表面上表達的受體濃度來進行辨別。不論是靶向藥物治療，還是病原體感染，選擇性地靶向細胞無疑是非常重要的。一套精準的靶向策略應能有效結合靶細胞的特定受體，但不結合（或者微弱地結合）其他細胞。

中國科學院物理研究所/北京凝聚態物理國家實驗室（籌）SM9組教授Jure Dobnikar、博士Tine Curk和劍橋大學教授Daan Frenkel共同合作，利用計算機模擬和統計學物理制定出一套最優多目標靶向的理論體系。

該理論的主要成果是設定簡單的規則，利用多價顆粒和靶細胞的受體特性來區分進而靶向靶細胞：

1）主體（靶細胞）上受體的高敏特性是通過多價性來實現的，而不是通過客體（遞送載體）上的配體和靶細胞上受體之間的強結合來實現的，客體包覆更多的配體只會使其與主體上的受體產生微弱的結合。

2）在客體和主體表面的濃度分布應是密度匹配的。

3）配體-受體間相互作用的有效值約為1.3 kBT。

不同於傳統的生物醫學方法，這項工作中制定的規則是首先識別一個標記（高表達受體），然後找到一個能夠有效並特定結合這個標記的配體（抗體）。抗體不具有選擇性，他們能夠強力依附在靶細胞上，同時也能夠依附在其他具有類似膜成分的細胞上。因此，在癌症治療中，藥物會被同時傳遞到癌細胞和健康細胞（如肝細胞、腎細胞等）上，嚴重製約了化療的效率。這表明，藥物的選擇性傳遞只能通過具有弱結合作用的多價載體來實現。這項工作所得到的結果證明，副作用明顯降低的定向性藥物傳遞是可以實現的。

該研究以Optimal multivalent targeting of membranes with many distinct receptors為題發表在《美國科學院院刊》上。這項研究受到來自中科院物理所和歐洲與英國的資助。