Abstract
BackgroundAreas of hypoxia are often found in triple-negative breast cancer (TNBC), it is thus more difficult to treat than other types of breast cancer, and may require combination therapies. A new strategy that combined bioreductive therapy with photodynamic therapy (PDT) was developed herein to improve the efficacy of cancer treatment. Our design utilized the characteristics of protoporphyrin IX (PpIX) molecules that reacted and consumed O2 at the tumor site, which led to the production of cytotoxic reactive oxygen species (ROS). The low microenvironmental oxygen levels enabled activation of a bioreductive prodrug, tirapazamine (TPZ), to become a toxic radical. The TPZ radical not only eradicated hypoxic tumor cells, but it also promoted therapeutic efficacy of PDT.ResultsTo achieve the co-delivery of PpIX and TPZ for advanced breast cancer therapy, thin-shell hollow mesoporous Ia3d silica nanoparticles, designated as MMT-2, was employed herein. This nanocarrier designed to target the human breast cancer cell MDA-MB-231 was functionalized with PpIX and DNA aptamer (LXL-1), and loaded with TPZ, resulting in the formation of TPZ@LXL-1-PpIX-MMT-2 nanoVector. A series of studies confirmed that our nanoVectors (TPZ@LXL-1-PpIX-MMT-2) facilitated in vitro and in vivo targeting, and significantly reduced tumor volume in a xenograft mouse model. Histological analysis also revealed that this nanoVector killed tumor cells in hypoxic regions efficiently.ConclusionsTaken together, the synergism and efficacy of this new therapeutic design was confirmed. Therefore, we concluded that this new therapeutic strategy, which exploited a complementary combination of PpIX and TPZ, functioned well in both normoxia and hypoxia, and is a promising medical procedure for effective treatment of TNBC.
Highlights
Areas of hypoxia are often found in triple-negative breast cancer (TNBC), it is more difficult to treat than other types of breast cancer, and may require combination therapies
Taken together, the synergism and efficacy of this new therapeutic design was confirmed. We concluded that this new therapeutic strategy, which exploited a complementary combination of protoporphyrin IX (PpIX) and TPZ, functioned well in both normoxia and hypoxia, and is a promising medical procedure for effective treatment of TNBC
Characterization of materials The as-synthesized MMT-2 displayed a characteristic XRD (X-ray diffraction) pattern that corresponded to Ia3d symmetry (Additional file 1: Figure S1), and the hollow morphology and the thin shell with ordered mesostructure of each nanoparticle could be observed by TEM (Fig. 1a)
Summary
Areas of hypoxia are often found in triple-negative breast cancer (TNBC), it is more difficult to treat than other types of breast cancer, and may require combination therapies. The TPZ radical eradicated hypoxic tumor cells, but it promoted therapeutic efficacy of PDT. TNBC remains a challenging subtype of breast cancer to treat, and its high rates of relapse are likely due to the presence of increased levels of cancer stem cells [6,7,8]. Targeting hypoxic cancer cells seems to be a plausible idea for treating TNBC. This phenomenon inspired us to utilize bioreductive drugs (BD) agents, which are inactive prodrugs that can be converted into potent cytotoxins under conditions of either low oxygen tension or in the presence of high levels of specific reductases, to develop new therapeutic strategies. Tumor cells may multiply farther away from the blood supply, which results in a relatively low oxygen tension of < 8 mm Hg (1 %) compared with a normal blood oxygen pressure of 70 mm Hg or 9.5 % [14]
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