INVERSIONES EN OBRAS, PROGRAMAS, TALLERES OFRECIDOS A LA PARROQUIA MEDIANTE EL PROYECTO ESTRATÉGICO MINERO LOMA
3.2 Beneficios a nivel local por concepto de regalías
3.3.2 EJES DE ACCIÓN: Aportes de la empresa minera
5.1: Summary of Current Work
In this work, we have synthesized a radio-theranostic nanoparticle capable of encapsulating a number of radiometals by virtue of their low solubility with phosphate. Because cationic atoms such as Lu, Y, and Cu are able to outcompete calcium for precipitation with phosphate in the nanoparticle cores, both very high and very low loading of isotope into LCP can be achieved without changing any other inputs. This not only allows flexibility and reproducibility among many different batch sizes and applications, but overcomes the scale-up barrier pervasive in the field of nanoparticle therapy, permitting human-scale synthesis on the benchtop. This high specific loading can be achieved in nanoparticles that are still overwhelmingly composed of calcium phosphate.
We have found that 177Lu-LCP is an effective SPECT and Cerenkov imaging agent, and monotherapy with 177Lu-LCP provides effective cancer therapy in two smaller tumor models. Tumor growth inhibition occurs by means of DNA double-stranded breaks that subsequently trigger apoptosis in tumor cells. Additionally, treatment with 177Lu-LCP can modify the tumor microenvironment by preventing the organization of fibroblasts into a more mature structure. Unfortunately, if treatment begins after this aggressive and resistant microenvironment forms, 177Lu-LCP alone is insufficient to decrease the tumor growth rate.
In order to treat these aggressive, desmoplastic tumors, a combination treatment strategy was devised, coupling 177Lu-LCP with the vascular disrupting agent CA4P. Monotherapy with CA4P causes massive hemorrhagic necrosis in sections of large tumors, but is unable to slow the overall tumor
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growth. We have found that treatment with CA4P three hours before treatment with 177Lu-LCP increases both the accumulation and retention of 177Lu-LCP in the tumor, increasing the overall dose of radiation to the tumor cells. The increased dose in the tumor helps maintain the apoptosis caused by the CA4P, leading to significant tumor growth inhibition in this aggressive model.
The moderate success of this combination therapy using the model radionuclide 177Lu prompted us to compare it to 90Y, a radionuclide with a higher emission of beta energy resulting in a longer path length of the beta particle in tissue. In a large tumor with inhomogenously delivered nanoparticles, the longer path length allows damage to cells in regions where nanoparticle accumulation is low. In addition, the high beta energy from 90Y provides grater damage per event than 177Lu. We found that combination therapy with 90Y-LCP and CA4P decreased tumor growth rate significantly more than 177Lu- LCP + CA4P, supporting our hypothesis. Seven days after treatment with 90Y-LCP + CA4P, these large, aggressive tumors were still slowly growing, although there was massive apoptosis and loss of fibroblast structure throughout the tumor. At this point, treatment with a low dose of cisplatin-loaded nanoparticles—at a dose that was ineffective in untreated tumors of a similar size—caused a near-total inhibition of tumor growth until cessation of treatment.
5.2: Significance and Novelty of Current Studies
As stated above, the high drug loading window of isotope-loaded LCP has the potential to overcome the significant barrier of nanoparticle scale-up. The ability for LCP to encapsulate a number of therapeutic or theranostic isotopes with alone or in combination with other therpautics—as demonstrated with 64Cu-GMP-LCP—provides a huge range of applications for this platform.
Internal radiation therapy provides an advantage over chemotherapy because while chemotherapy must be delivered into a cell to provide its effect, beta particles (or other decay products) can travel and deposit energy many cell lengths away from the source. Because nanoparticles are not
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homogenously delivered in vivo, radiation therapy is well-equipped to maximize the number of cells receiving treatment. We have shown in Chapter 2 that although nanoparticles are delivered to the tumor inhomogenously, nearly all cells in the analyzed sections are within just 50 μm of the nearest nanoparticle, suggesting that all cells are within striking distance of a beta decay from 177Lu, which has an average beta path length of 200-300 μm.
Regarding our combination therapy, the ability of CA4P to increase nanoparticle accumulation and retention in tumors can not only be extended to other versions of LCP, but can potentially be carried out in combination with completely different nanoparticle formulations. By allowing greater nanoparticle accumulation while subsequently causing massive areas of apoptosis in tumors, CA4P has the potential to become a player alongside nanoparticle formulations in the clinic.
5.3: Future Expectations
Clinical implementation of this combination therapy must be modified to minimize systemic toxicity. While intravenous administration of 90Y-LCP presents a good model of internal radiation therapy’s effectiveness in combination with CA4P, the well-known uptake of nanoparticles into clearing organs presents a compelling argument against this injection route. Perhaps the best future use for 177Lu/90Y-LCP is in selective internal radiation therapy (SIRT) [128, 129]. SIRT locally delivers 90Y- microspheres around primary or metastatic tumors in the liver via a catheter placed into the hepatic artery. The large size of the microspheres prevents them from entering the tumor capillaries, so a larger dose must be given in order to provide treatment to all tumor cells, resulting in off-target toxicity to the liver and lung. Local delivery of 177Lu/90Y-LCP via hepatic catheter may result in better tumor penetration than 90Y-microspheres and less off-target dose than systemic administration of LCP, increasing the dose to the hepatic tumor while decreasing off-target effects. Combination therapy with CA4P against stroma-rich, desmoplastic tumors would not only cause massive apoptosis in the tumor
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centers, but also induce an increased accumulation of nanoparticles in the tumor and prime the tumor microenvironment for further treatment using small molecule drugs such as cisplatin that are ineffective without combination therapy.
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