Transport cocktails for cancer therapeutics

Beyond biological cell heterogeneity, evidenced by different resistances to therapeutics, “delivery heterogeneity” crucially limits treatment efficacy for advanced solid tumors: variations in therapeutic drug delivery to different tumor areas (perivascular, perinecrotic) leading to nonuniform drug concentrations/doses and to unsuccessful treatment (cancer cell kill). Short-range (40–80 <a:math xmlns:a="http://www.w3.org/1998/Math/MathML"> <a:mrow> <a:mi>µ</a:mi> <a:mi mathvariant="normal">m</a:mi> </a:mrow> </a:math> ), high energy (1–5 MeV) <c:math xmlns:c="http://www.w3.org/1998/Math/MathML"> <c:mi>α</c:mi> </c:math> particles successfully address the biological heterogeneity: the double-strand DNA breaks they cause make them impervious to cell resistance mechanisms. Multiresponsive nanocarriers and/or engineered antibody-drug-conjugates are elegant approaches to delivering such <d:math xmlns:d="http://www.w3.org/1998/Math/MathML"> <d:mi>α</d:mi> </d:math> -particle emitters. Delivery heterogeneity, however, remains a challenge in established (i.e., large, vascularized) tumors. Remarkably, delivery properties enabling efficacy at the cell scale (targeting selectivity, affinity, cell drug uptake) may act against spatial delivery uniformity at the tumor scale (binding-site barrier effect). We have previously demonstrated, in different mouse models, that spatial delivery uniformity, key to the effective killing of solid tumors, can be achieved utilizing combinations of different, distinct delivery carriers of the same emitter, but with different, complementary delivery properties, “leaving no cancer cell behind.” We build first principles reaction-transport models (quantitatively informed by experiments) that explain the “geographically complementary” behaviors of such carrier cocktails, and help optimally design these cocktails and their delivery protocols. Published by the American Physical Society 2024