ABSTRACT
The efficacy of dose-enhancing gold nanoparticles (AuNPs) is negatively impacted by low tumor uptake, low cell membrane penetration, limited diffusion distance, and short lifetime of radiation-induced secondary particles. To overcome these limitations, we have developed a novel AuNP system capable of radiation-triggered release of nitrite, a precursor of reactive nitrogen species, and report here on the in vivo characterization of this system. AuNPs were functionalized through PEGylation, cell-penetrating peptides (CPP; AuNP@CPP), and nitroimidazole (nIm; AuNP@nIm-CPP). Mice with subcutaneous 4T1 tumors received either AuNP@nIm-CPP or AuNP@CPP intraperitoneally. Tumor and normal tissue uptake were evaluated 24 h post AuNP administration. A separate cohort of mice was injected and irradiated to a single-fraction dose of 18 Gy in a 225 kVp small animal irradiator 24 h post NP administration. The mice were followed for two weeks to evaluate tumor response. The mean physical and hydrodynamic size of both NP systems were 5 and 13 nm, respectively. NP nIm-loading of 1 wt% was determined. Tumor accumulation of AuNP@nIm-CPP was significantly lower than that of AuNP@CPP (0.2% vs 1.2%, respectively). In contrast, AuNP@nIm-CPP showed higher accumulation compared to AuNP@CPP in liver (16.5% vs 6.6%, respectively) and spleen (10.8% vs 3.1%, respectively). With respect to tumor response, no differential response was found between non-irradiated mice receiving either saline or AuNP@nIm-CPP alone. The combination of AuNP@CPP+ radiation showed no differential response from radiation alone. In contrast, a significant delay in tumor regrowth was observed in mice receiving AuNP@nIm-CPP+ radiation compared to radiation alone. AuNP functionalized with both CPP and nIm exhibited an order of magnitude less tumor accumulation compared to the NP system without nIm yet resulted in a significantly higher therapeutic response. Our data suggest that by improving the biokinetics of AuNP@nIm-CPP, this novel NP system could be a promising radiosensitizer for enhanced therapeutic response following radiation therapy.
Subject(s)
Breast Neoplasms/therapy , Gamma Rays , Gold/chemistry , Metal Nanoparticles/administration & dosage , Nitrites/metabolism , Radiation-Sensitizing Agents/administration & dosage , Reactive Nitrogen Species/metabolism , Animals , Apoptosis , Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Cell Proliferation , Combined Modality Therapy , Female , Humans , Metal Nanoparticles/chemistry , Mice , Mice, Nude , Radiation-Sensitizing Agents/chemistry , Tumor Cells, Cultured , Xenograft Model Antitumor AssaysABSTRACT
BACKGROUND: Vulvar varicosities (VV) are dilated and tortuous veins occurring within the external female genitalia. Patients may seek treatment of these varices for both medical and cosmetic purposes. In some patients, VV may be associated with a chronic pelvic pain syndrome called pelvic congestion syndrome (PCS). OBJECTIVE: To review the English language literature on VV in both pregnant and nonpregnant women. MATERIALS AND METHODS: A literature search pertaining to vulvar varicosities and PCS was performed using PubMed and Google Scholar databases. RESULTS: There is an overall paucity of literature discussing VV, particularly in nonpregnant women without PCS. Management options for VV include compression, sclerotherapy, embolization, and surgical ligation. Treatment can be dependent on the coexistence of pelvic or leg varicosities and may require referral to a vein specialist for advanced imaging techniques and procedures. Direct sclerotherapy to VV may not provide adequate treatment if pelvic or leg varices are also present. CONCLUSION: In women with persistent VV, imaging studies should be obtained before treatment to evaluate the surrounding venous anatomy of the pelvis and leg, as the results often affect the treatment approach. Patients presenting with VV and chronic pelvic pain should be evaluated for PCS.
