Development and evaluation of an ultrasound-triggered microbubble combined transarterial chemoembolization (TACE) formulation on rabbit VX2 liver cancer model.

Transarterial chemoembolization (TACE) is an image-guided locoregional therapy used for the treatment of patients with primary or secondary liver cancer. However, conventional TACE formulations are rapidly dissociated due to the instability of the emulsion, resulting in insufficient local drug concentrations in the target tumor. Methods: To overcome these limitations, a doxorubicin-loaded albumin nanoparticle-conjugated microbubble complex in an iodized oil emulsion (DOX-NPs-MB complex in Lipiodol) has been developed as a new ultrasound-triggered TACE formulation. Results: (1) Microbubbles enhanced therapeutic efficacy by effectively delivering doxorubicin- loaded nanoparticles into liver tumors via sonoporation under ultrasound irradiation (US+). (2) Microbubbles constituting the complex retained their function as an ultrasound contrast agent in Lipiodol. In a rabbit VX2 liver cancer model, the in vivo study of DOX-NPs-MB complex in Lipiodol (US+) decreased the viability of tumor more than the conventional TACE formulation, and in particular, effectively killed cancer cells in the tumor periphery. Conclusion: Incorporation of doxorubicin-loaded microbubble in the TACE formulation facilitated drug delivery to the tumor with real-time monitoring and enhanced the therapeutic efficacy of TACE. Thus, the enhanced TACE formulation may represent a new treatment strategy against liver cancer.

Focused ultrasound-triggered chemo-gene therapy with multifunctional nanocomplex for enhancing therapeutic efficacy.

Nanotechnology-based combination therapies, especially chemo-gene therapy, have been spotlighted as promising alternatives for cancer therapy. However, only a small amount of systemically administered nanomedicines reach the tumor site by the enhanced permeability and retention (EPR) effect, resulting in the limited therapeutic efficacy. Furthermore, the design of ideal drug delivery system for chemo-gene therapy has been impeded by the chemical and physical differences between nucleic acids and chemotherapeutics. Herein, we report a precisely designed nanocomplex which exhibits a focused ultrasound (FU)-responsive release and enhanced accumulation of released therapeutics to tumor site. After the nanocomplex composed of siRNA nanoparticles (siRNA-NP) and chemotherapeutics-loaded microbubbles was systemically injected, the nanocomplex was collapsed around the tumor tissue by FU exposure, and both siRNA-NP and chemotherapeutics were penetrated the dense extracellular matrix (ECM) of tumor site, leading to the enhanced chemo-gene therapeutic efficacy. The two-in-one nanocomplex is expected as a promising platform for combination therapy that can enhance the therapeutic efficiency of combination drugs at the cell and/or tissue levels with high drug loading ratio.

The efficacy of porous hydroxyapatite chips as gap filling in open-wedge high tibial osteotomy in terms of clinical, radiological, and histological criteria.

PURPOSE: Hydroxyapatite (HA) does not fully degrade, which raises concerns about poor remodeling and incorporation into the bone after open-wedge high tibial osteotomy (HTO). The purpose of this study was to compare the results between gap filling with allogenous chip bone and HA chip after open-wedge HTO using propensity score matching and to analyze the radiological unabsorbed area of opening gaps histologically in HA using patients. METHODS: The matched variables were age, body mass index, sex, correction angle, and smoking status. After matching, the allogenous group and HA group included 33 patients each with two years of follow-up. The range of motion (ROM), International Knee Documentation Committee (IKDC) subjective score, Knee Injury and Osteoarthritis Outcome Score (KOOS), mechanical axis (MA), tibial slope, osteoconductivity, and absorbability were evaluated and compared between both groups. Among the HA group, 20 patients underwent bone biopsy and histologically analyzed of the radiological unabsorbed area. RESULTS: The postoperative ROM, IKDC subjective score, and KOOS were similar in both groups. The osteoconductivities did not differ significantly. The absorbability in the HA group was significantly lower than allogenous group (59.6% vs. 22.6%, P < .001). The histological sections of the radiological unabsorbed area showed mature lamelliform bone tissues were significantly greater than structurally degraded remnant HA (30.4% and 4.2%, P < .001). CONCLUSION: The HA chips showed an inferior absorbability, however, a mature lamelliform bone was observed in significantly larger amounts than remnant HA in the radiological unabsorbed area. The allogenous bone chips and HA chips showed similar clinical and radiological results after open-wedge HTO.

Outcomes of Total Hip Arthroplasty in Patients with Osteonecrosis of the Femoral Head Following Surgical Treatment of Brain Tumors.

Corticosteroids have been widely used in patients with brain tumors to reduce tumor-associated edema and neurological deficits. This study examined the outcomes of total hip arthroplasty (THA) in patients with osteonecrosis of the femoral head (ONFH) following brain tumor surgery. We identified 34 THAs performed in 26 patients with steroid-induced ONFH among 9254 patients undergoing surgical treatment for primary brain tumors. After propensity score matching with demographics, 68 THAs (52 patients) in ONFH unrelated to brain tumors were selected as the control group. At the time of THA, 54% of brain tumor patients had neurological sequelae and 46% had adrenal insufficiency. After THA, patients with brain tumor required longer hospital stay, reported a lower functional score, and showed a higher rate of heterotopic ossification compared to the control group. However, hip pain score improved significantly after THA in the brain tumor group, and did not differ from that of the control group (P-value = 0.168). Major complication rates were similar (2.9% and 1.5% for the brain tumor and control groups, respectively; P-value = 1.000), and implant survivorships were not different at 7 years (100% and 98.1% for the brain tumor and control groups, respectively; P-value = 0.455). Our findings suggest that THA can be safely performed to reduce hip pain in patients with steroid-induced ONFH after surgical treatment of primary brain tumors.

Epigenetic suppression of the anti-aging gene KLOTHO in human prostate cancer cell lines.

KLOTHO was originally identified as an aging-suppressor gene that causes a human aging-like phenotype when tested in KLOTHO-deficient-mice. Recent evidence suggests that KLOTHO functions as a tumor suppressor by inhibiting Wnt signaling. KLOTHO gene silencing, including DNA methylation, has been observed in some human cancers. Aberrant activation of Wnt signaling plays a significant role in aging, and its silencing may be related to prostate cancer and other types of cancers. Thus, we investigated whether the expression of the anti-aging gene KLOTHO was associated with epigenetic changes in prostate cancer cell lines. KLOTHO mRNA was detected in the 22Rv1 cell line while it was not detected in DU145 and PC-3 cell lines. The restoration of KLOTHO mRNA in the DU145 and PC-3 cell lines was induced with a DNA methyltransferase inhibitor. Methylation-specific PCR was performed to determine the specific CpG sites in the KLOTHO promoter responsible for expression. In addition, the level of methylation was assessed in each CpG by performing bisulfite sequencing and quantitative pyrosequencing analysis. The results suggested a remarkable inverse relationship between KLOTHO expression and promoter methylation in prostate cancer cell lines.