(636d) Combination of Targeting-Driven and Diffusion-Driven Carriers to Address Delivery Heterogeneities in Pancreatic Cancer Solid Tumors

Introduction: Pancreatic Ductal Adeno Carcinoma (PDAC) is one of the most lethal types of cancer in humans. Given its aggressive nature and higher resistance observed to various existing treatment approaches, PDAC has become one of the most challenging cancers to treat. Clinical studies with α-particle emitters have sometimes had exceptional outcomes on patients with advanced metastatic prostate cancer resistant to approved options. We evaluate a novel strategy to deliver α-particles to established PDAC so as to inhibit tumor growth and prolong survival in mice.

We use α-particles because of their ability to cause double strand DNA breaks that unequivocally result in cell death, making α-particle radiopharmaceutical therapy (αRPT) impervious to resistance if optimally delivered. A major advantage and a key challenge of αRPT is the short range of α-particles in tissue (5-10 cell diameters). Although it makes them ideal for precise localization of irradiation, the limited penetration depths within solid tumors of traditional αRPT carriers (antibodies and/or conventional nanoparticles) result in only partial tumor irradiation. And for αRPT, tumor regions not being hit by the delivered α-particles will likely not be killed. The partial tumor irradiation is currently the cause of treatment failure with α-particle therapy.

We evaluate our newly discovered strategy to enable uniform and prolonged irradiation of the entire volume of vascularized PDAC solid tumors. Our delivery strategy is grounded in a strikingly simple and potentially powerful idea: we simultaneously deliver the same α-particle emitter by different carriers, each best killing different/complementary regions of the same (large) tumor. We use the α-particle generator Actinium-225 (²²⁵Ac), and we combine (1) a tumor-responsive lipid nanoparticle (NP) that upon tumor uptake releases in the interstitium a highly-diffusing form of its radioactive payload (²²⁵Ac-DOTA), which penetrates the deeper parts of tumors where antibodies do not reach, with (2) a separately administered, less-penetrating radiolabeled-antibody irradiating the tumor perivascular regions from where the NP’s contents clear too fast.

Materials and Methods:

In vitro, on spheroids formed by PANC-1 PDAC cells, and used as surrogates of the avascular regions of solid tumors, the dose split ratios delivered by the two carriers (the tumor-responsive lipid nanoparticles and the antibody) were varied, and the effect on spheroid (out)growth was evaluated and was correlated to the corresponding ²²⁵Ac spatiotemporal microdistributions. On NOD Scid Gamma (NSG) mice bearing BxPC-3 PDAC subcutaneous xenografts, tumor growth inhibition and survival was evaluated following administration of α-particle therapy – while keeping constant the total radioactivity per animal – delivered by combinations of the two separate carriers and by each carrier alone.

Results and Discussion: In spheroids of variable sizes at initiation of treatment, best suppression of growth was achieved by those combinations of carriers – at same total radioactivity concentration - that collectively resulted in more uniform spatiotemporal microdistributions of delivered ²²⁵Ac. In animals, for the same total administered radioactivity, our strategy to split the radioactivity into two separately administered carriers best inhibited the growth of BxPC-3 pancreatic cancer xenografts and significantly prolonged the survival of tumor-bearing NSG mice compared to the survival of animals that were administered the same total radioactivity delivered by the individual carriers alone (Figure 1).

Conclusions: Based on our findings, it can be concluded that the combination of delivery carriers resulting in complementary microdistributions of the same drug within solid tumors results in more uniform intratumoral drug distributions affecting/killing larger numbers of cancer cells within the tumor and, thus, prolongs survival of PDAC tumor-bearing mice compared to the same total administered drug delivered exclusively by each carrier alone.