Photothermal-chemotherapy with doxorubicin-loaded hollow gold nanospheres: A platform for near-infrared light-trigged drug release.

Photothermal ablation (PTA) is an emerging technique that uses near-infrared (NIR) laser light-generated heat to destroy tumor cells. However, complete eradication of tumor cells with PTA is difficult because of uneven heat distribution in the treatment volume. We hypothesized that combining PTA with chemotherapy using a single multifunctional nanoconstruct that mediates simultaneous photothermal cell killing and drug release (photothermal-chemotherapy) would result in enhanced antitumor activity and reduced toxicity compared to chemotherapy alone. Doxorubicin (DOX) was loaded to hollow gold nanospheres (HAuNS) coated with polyethylene glycol (PEG). The pharmacokinetics and biodistribution of both DOX and HAuNS in the resulting nanoconstruct, DOX@PEG-HAuNS having different DOX:PEG:HAuNS ratios, were evaluated using dual isotope labeling techniques. The antitumor activity of DOX@PEG-HAuNS with DOX:PEG:HAuNS weight ratio of 1:3:1 (NP3) in combination with NIR laser was studied in vitro and in vivo using human MDA-MB-231 breast cancer and A2780 ovarian cancer cells. In vitro, NP3 mediated PTA of both cancer cells and DOX release upon NIR laser treatment. In vivo, NP3 showed slower clearance in blood and greater accumulation in tumors than free DOX. NP3-plus-NIR laser demonstrated greater antitumor activity than free DOX, NP3, or liposomal DOX. Moreover, NP3 displayed significantly decreased systemic toxicity compared to free DOX or liposomal DOX. Enhanced antitumor effect with NP3-plus-laser can be attributed to both the cytotoxic effect of DOX released from NP3 and the photothermal effect mediated by HAuNS. Slow release of DOX from NP3 in normal tissues contributed to reduced systemic toxicity. Photothermal-chemotherapy exemplified by a single-agent nanoconstruct NP3 is a promising approach to anticancer therapy.

Hepatic arterial embolization with doxorubicin-loaded superabsorbent polymer microspheres in a rabbit liver tumor model.

OBJECTIVES: The pharmacokinetic profile after hepatic arterial embolization with superabsorbent microspheres (QuadraSpheres) loaded with doxorubicin was studied. METHODS: Rabbits with hepatic VX2 tumors were treated with intra-arterial administration of QuadraSpheres loaded with doxorubicin, or transarterial chemoembolization (TACE) using doxorubicin, Lipiodol and Embospheres, or hepatic arterial infusion (HAI) of doxorubicin. Tumor specimens were evaluated by fluorescence microscopy, and plasma and tumor concentrations of doxorubicin were measured. RESULTS: The peak plasma concentration of doxorubicin was lower in the QuadraSphere group (309.9 ng/ml) than in the HAI (673.4 ng/ml) or TACE (360.5 ng/ml) groups, suggesting higher tumor retention in the QuadraSphere group. Intratumoral doxorubicin levels declined to negligible levels at 1 and 3 days after treatment, respectively, in the HAI and TACE groups. In the QuadraSphere groups, intratumoral doxorubicin level declined after day 1, but was still detectable at 14 days after treatment and was higher than that in the other groups at 1, 3, and 7 days. Intratumoral doxorubicin fluorescence was detected at all time points in the QuadraSphere group, but only at 1 day after treatment in the TACE group. CONCLUSIONS: Hepatic arterial administration of doxorubicin-loaded QuadraSpheres enables the sustained release of doxorubicin to hepatic tumors.

Transcatheter arterial embolization of renal VX-2 carcinoma: ethiodol-ethanol capillary embolization combined with carboplatin.

OBJECTIVE: We wanted to determine whether transcatheter Ethiodol-based capillary embolization in combination with carboplatin could improve the efficiency of a 1:1 Ethiodol-ethanol mixture (EEM) to ablate kidneys that been inoculated with VX-2 carcinoma. MATERIALS AND METHODS: The right kidney in 34 New Zealand white rabbits were inoculated with fresh VX-2 tumor fragments. One week later, the kidneys were subjected to transarterial treatment (4-5 rabbits/group): Saline infusion (Group 1); carboplatin infusion (5 or 10 mg, Groups 2A and 2B); carboplatin-Ethiodol (CE) alone (Group 3) and followed by main renal artery occlusion with ethanol (RAO) (Group 4); carboplatin-EEM (C-EEM) followed by RAO (Group 5); carboplatin infusion followed by EEM plus RAO (Group 6); and EEM followed by RAO (Group 7). The animals were followed for up to 3-weeks. The treated kidneys were evaluated angiographically and macroscopically. The kidneys that showed successful embolization macroscopically were entirely cut into serial sections, and these were examined microscopically. Histologically, the kidneys were evaluated on the basis of the residual tumor found in the serial sections. RESULTS: The results obtained with carboplatin infusion alone (Groups 2A and 2B) and CE without RAO (Group 3) were similar to those of the control animals (Group 1). Kidneys from Groups 4-7 demonstrated macroscopically successful embolization with histologically proven complete renal parenchyma infarction; however, some residual tumor was evident in all but one animal. CONCLUSION: None of the Ethiodol-based modalities combined with locoregional carboplatin were more efficacious for tumor ablation than EEM alone.

Inhibition of prostate cancer-meditated osteoblastic bone lesions by the low-calcemic analog 1alpha-hydroxymethyl-16-ene-26,27-bishomo-25-hydroxy vitamin D3.

Prostate cancer metastasizes almost exclusively into the bone whereby it induces primarily an osteoblastic response. Non-calcemic vitamin D analogs have been shown to inhibit proliferation of prostate cancer cells in culture and inhibit their growth as subcutaneous xenografts in mice. However, their effect on prostate cancer cell growth in the bone has not been examined. In the present study, we inoculated the osteoblastic prostate cancer cell line MDA-PCa 2b into the bone of male SCID mice and examined the effect of the low-calcemic hybrid analog 1alpha-hydroxymethyl-16-ene-26,27-bishomo-25-hydroxy vitamin D(3) (JK-1626-2) on their ability to induce bone lesions. We found that 7 weeks after inoculation of MDA-PCa 2b cells, 90% of the mice in the vehicle-treated group had significant bone lesions that were detectable by micro-computed tomography and characterized by thickening of the cortical bone and ossification of the epiphysis. Only 30% of the mice in the analog-treated group (daily injections of 4microg/kg, 5 days/week for up to 7 weeks) had detectable bone lesions. Histological examination of the decalcified tumor-bearing bones has shown that tumor cells completely replaced the bone marrow in the diaphysis, and destroyed the trabecular bone in the metaphysis in 90% of the vehicle-treated mice. In contrast, the metaphysis of 60% of analog-treated mice appeared normal, although tumor cells were still found in the diaphysis of 70% of the bones in the analog-treated group. There was no evidence of hypercalcemia in any of the analog-treated mice. In a co-culture, MDA-PCa 2b cells induced a profound mitogenic response in osteoblasts followed by enhanced differentiation. However, in the presence of the analog the mitogenic response of the osteoblasts to the malignant cells was significantly attenuated. These experiments led to the hypothesis that, in vivo, JK-1626-2 prevented the metastatic bone lesions by inhibiting the mitogenic response of osteoblasts to growth factors produced by MDA-PCa 2b cells.

Ethiodized oil-ethanol capillary embolization in rabbit kidneys: temporal histopathologic findings.

PURPOSE: To determine the temporal histopathologic findings associated with selective arterial injection of a 1:1 ethiodized oil-ethanol mixture (EEM) in normal rabbit kidney followed by administration of pure ethanol into the main renal artery. MATERIALS AND METHODS: In five rabbits, the EEM was injected sequentially into each segmental renal artery of the right kidney until capillary stasis occurred. Pure ethanol was then injected into the main renal artery to achieve complete arterial stasis. Before sacrifice, the left kidney in each animal was acutely (ie, with a short follow-up period) embolized by using the same technique. The 10 kidneys of the five rabbits were evaluated microscopically at 1 (n = 3), 1(1/2) (n = 1), and 3 hours (n = 1) and 1 (n = 1), 3 (n = 1), 5 (n = 1), 7 (n = 1), and 14 days (n = 1) after embolization. RESULTS: Injection of the EEM (mean volume, 0.46 mL +/- 0.14 [SD]) followed by ethanol alone (mean volume, 0.25 mL +/- 0.09) led to complete stasis in all kidneys. There was no recanalization in the chronically (ie, with a longer follow-up period) embolized kidneys. Microscopically, uniform distribution of the EEM was evident in all slices at all time points. From 1 to 3 hours, sloughing of endothelium, formation of thrombi, and deposition of eosinophilic material along the renal, interlobar, and arcuate arteries were observed, without evidence of parenchymal damage. Within 24 hours, complete coagulative necrosis of the entire kidney occurred as a result of an occluding thrombus in the main renal artery. Analysis at subsequent time points revealed liquefaction of necrotic tissue and replacement with granulation tissue. CONCLUSION: In the rabbit, selective renal arterial injection of EEM followed by administration of ethanol produces vascular endothelial damage initiating thrombosis that results in renal infarction and ablation within 24 hours.