Bhatavdekar, O. | Search bioRxiv

bioRxiv2024

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 {micro}m), high energy (1-5 MeV) alpha-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 alpha-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 effect1). 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.

cancer biology↗

bioRxiv2023

Combined, yet Separate: cocktails of carriers (not drugs) for α-particle therapy of solid tumors expressing moderate-to-low levels of targetable markers

Alpha-particle radionuclide-antibody conjugates are being clinically evaluated against solid cancers expressing moderate levels of the targeted markers, with promising results. These findings are attributed to the high killing power of alpha-particles in spite of the expected decrease in antibody tumor uptake, that reduces tumor absorbed doses. However, when tumor absorbed doses are reduced, addressing the heterogeneities in delivery of alpha-particles within solid tumors (i.e. enabling uniform irradiation patterns) becomes critical: to maintain efficacy, the fewer alpha-particles delivered within tumors need to traverse/hit as many different cancer cells as possible. This proof-of-concept study describes an approach to complement the antibody- targeted radiotherapy by using a separate carrier to deliver a fraction of the injected radioactivity to tumor regions geographically different than those affected by the antibody; collectively, the two carriers should distribute the alpha-particle emitters, Actinium-225 in particular, more uniformly within tumors maintaining efficacy. MethodsWe monitored the extent(s) of tumor growth inhibition, onset delay of spontaneous metastases and/or survival on orthotopic MDA-MB-213 and MDA-MB-436 triple negative breast cancer mouse models and on an ectopic BxPC3 pancreatic cancer mouse model, treated systemically with the two separate carriers. Tumors were chosen to express different (but low) levels of HER1, utilized as a model antibody-targeted marker. ResultsIndependent of tumor origin and/or resistance to chemotherapy, the two separate carriers: (a) improved the primary tumor growth inhibition, (b) eliminated the formation of spontaneous metastases, and/or (c) prolonged survival, at lower or comparable tumor delivered doses relative to the antibody alone, without noticeable off-target toxicities. ConclusionThis tumor-agnostic strategy is timely and could be used to enhance the efficacy of existing alpha-particle radionuclide-antibody treatments without increasing, possibly even reducing, the total administered radioactivity.

bioengineering↗