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

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 um), 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.

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Glioblastoma Treatment by Systemic Actinium-225 α-particle Dendrimer-radioconjugates is Improved by Chemotherapy

Nair,

Sarkar,

Hariharan

et al. 2024

Preprint

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RATIONALE: The poor prognosis of glioblastoma is largely due to drug resistance and tumor location that, together, make it difficult to treat aggressively without affecting the rest of the brain. METHODOLOGY: High-energy, short-range (40-80μm) dendrimer-delivered α-particles could address both challenges, because (1) they cause complex, highly cytotoxic double-strand DNA breaks, and (2) irradiation of the neighboring brain is minimal, since dendrimers selectively delivers them to tumors. Since cancer cells that are not directly hit by α-particles will likely not be killed, the patterns of tumor irradiation affect efficacy. Systemically injected dendrimers extensively accumulate in glioblastomas, where they are taken up by tumor associated macrophages (TAMs), which tend to infiltrate tumors. We hypothesized that dendrimers labeled with α-particle emitters, when being carried by TAMs, could more evenly irradiate glioblastomas, improving survival. In this study, the efficacy of dendrimers radiolabeled with the α-particle emitter actinium-225 (dendrimer-radioconjugates) was evaluated when administered alone and/or after temozolomide, in a syngeneic immune-competent orthotopic GL261-C57BL/6 mouse model. RESULTS: Systemically-administered dendrimer-radioconjugates, at activities that did not result in long-term toxicities, prolonged survival of mice with orthotopic GL261 tumors, compared to standard-of-care temozolomide (39 vs 31 days mean survival, p=0.0061) and non-treated animals (30 days, p=0.0009). Importantly, injection of temozolomide 24 hours before administration of dendrimer-radioconjugates further improved survival remarkably (44 days). This improvement in efficacy was attributed to: (1) the significant increase (by 33%) in tumor absorbed doses delivered by dendrimer-radioconjugates when injected after chemotherapy, without altering normal organ dosimetry, while sparing the tumor-surrounding healthy brain; (2) the potentially deeper tumor penetration of dendrimer-radioconjugates, suggested by the enhancement of dendrimer penetration within GL261-spheroids, employed as model tumor-avascular regions and/or TAM-free regions; and/or (3) the formation of a more lethal cocktail when both modalities acted on same cancer cells, that was correlated with increased levels of dendrimer-radioconjugates associating with GL261 cells in vitro and with greater incidences of karyomegaly in vivo. CONCLUSIONS: This study demonstrates the potential of a 'brain tumor targeted' systemic actinium-225 radiopharmaceutical therapy that inhibits growth of glioblastoma cells and prolongs survival of mice with orthotopic brain tumors, further improved by standard-of-care temozolomide, without notable toxicities.

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

Cited by 3 publications

References 26 publications

Combined, yet separate: cocktails of carriers (not drugs) for actinium-225 α-particle therapy of solid tumors expressing moderate-to-low levels of targetable markers

Combined, yet separate: cocktails of carriers (not drugs) for actinium-225 α-particle therapy of solid tumors expressing moderate-to-low levels of targetable markers

Transport Cocktails for Cancer Therapeutics

Glioblastoma Treatment by Systemic Actinium-225 α-particle Dendrimer-radioconjugates is Improved by Chemotherapy

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