The role of radiation-induced bystander effects in radiation therapy remains unclear. With renewed interest in therapy with alpha-particle emitters, and their potential for sterilizing disseminated tumor cells (DTCs), it is critical to determine the contribution of bystander effects to the overall response so they can be leveraged for maximum clinical benefit. Methods: Female Foxn1(nu) athymic nude mice were administered 0, 50, or 600 kBq/kg (RaCl2)-Ra-223 to create bystander conditions. At 24 hours after administration, MDA-MB-231 or MCF-7 human breast cancer cells expressing luciferase were injected into the tibial marrow compartment. Tumor burden was tracked weekly via bioluminescence. Results: The MDA-MB-231 xenografts were observed to have a 10-day growth delay in the 600 kBq/kg treatment group only. In contrast, MCF-7 cells had 7-and 65-day growth delays in the 50 and 600 kBq/kg groups, respectively. Histologic imaging of the tibial marrow compartment, alpha-camera imaging, and Monte Carlo dosimetry modeling revealed DTCs both within and beyond the range of the alpha-particles emitted from Ra-223 in bone for both MCF-7 and MDA-MB-231 cells. Conclusion: Taken together, these results support the participation of Ra-22(3)-induced antiproliferative/cytotoxic bystander effects in delayed growth of DTC xenografts. They indicate that the delay depends on the injected activity and therefore is dose-dependent. They suggest using (RaCl2)-Ra-223 as an adjuvant treatment for select patients at early stages of breast cancer.
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Beyond Antiresorptive Activity: Risedronate-Based Coordination Complexes To Potentially Treat Osteolytic Metastases
Coordination of clinically employed bisphosphonate, risedronate (RISE), to bioactive metals, Ca2+, Mg2+, and Zn2+,
allowed the formation of bisphosphonate-based coordination
complexes (BPCCs). Three RISE-based BPCCs, RISE-Ca, RISEMg, and RISE-Zn, were produced, and their structures were
elucidated by single crystal X-ray difraction. Interestingly, the
addition of an auxiliary ligand, etidronic acid (HEDP), resulted in
the recrystallized protonated form of the ligand, H-RISE. The pH-dependent structural stability of the RISE-based BPCCs was
measured by means of dissolution profles under neutral and acidic
simulated physiological conditions (PBS and FaSSGF, respectively). In comparison to RISE (Actonel), the complexes showed a
lower equilibrium solubility (∼70−85% in 18−24 h) in PBS, while a higher equilibrium solubility (∼100% in 3 h) in acidic media.
The results point to the capacity to release this BP in a pH-dependent manner from the RISE-based BPCCs. Subsequently, the
particle size of RISE-Ca was reduced, from 300 μm to ∼350 d.nm, employing the phase inversion temperature (PIT)-nanoemulsion
method, resulting in nano-Ca@RISE. Aggregation measurements of nano-Ca@RISE in 1% fetal bovine serum (FBS):H2O was
monitored after 24, 48, and 72 h to study the particle size longevity in physiological media, showing that the suspended material has
the potential to maintain its particle size over time. Furthermore, binding assays were performed to determine the potential binding
of nano-Ca@RISE to the bone, where results show higher binding (~1.7×) for the material to hydroxyapatite (HA, 30%) when
compared to RISE (17%) in 1 d. The cytotoxicity efects of nano-Ca@RISE were compared to those of RISE against the human
breast cancer MDA-MB-231 and normal osteoblast-like hFOB 1.19 cell lines by dose−response curves and relative cell viability
assays in an in vitro setting. The results demonstrate that nano-Ca@RISE signifcantly decreases the viability of MDA-MB-231 with
high specifcity, at concentrations ∼2−3× lower than the ones reported employing other third-generation BPs. This is supported by
the fact that when normal osteoblast cells (hFOB 1.19), which are part of the tissue microenvironment at metastatic sites, were
treated with nano-Ca@RISE no signifcant decrease in viability was observed. This study expands on the therapeutic potential of
RISE beyond its antiresorptive activity through the design of BPCCs, specifcally nano-Ca@RISE, that bind to the bone and degrade
in a pH-dependent manner under acidic conditions
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- Award ID(s):
- 1757365
- NSF-PAR ID:
- 10398422
- Date Published:
- Journal Name:
- ACS Applied Bio Materials
- ISSN:
- 2576-6422
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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- Free Publicly Accessible Full Text
-
Accepted Manuscript1.0
- Journal Article:
- https://doi.org/10.1021/acsabm.2c00648
