Enhanced drug retention in VX2 tumors by use of degradable starch microspheres

Twenty-nine rabbits with 12- to 14-day-old VX2 tumors in the hind leg were injected intraarterially with technetium-99m (99mTc) DTPA and various combinations of biodegradable starch microspheres, Spherex (Pharmacia, Sweden), to evaluate the efficacy of the microspheres in enhancing tumor retention of 99mTc DTPA. A gamma camera and nuclear medicine computer were used to generate time activity curves of 99mTc DTPA concentration in the tumors. Blood flow to the tumor and various muscles was also measured at intervals by left ventricular injection of 15 micron radiolabeled plastic microspheres. Ninety minutes following the administration of 99mTc DTPA, specimens from the tumor, plasma and different muscles were counted in a NaI well counter connected to a multichannel analyzer. When biodegradable microspheres mixed with 99mTc DTPA were injected and followed by a slow infusion of plain starch microspheres, the 99mTc DTPA was retained in the tumor at concentrations up to 11 times that seen when 99mTc DTPA alone was injected; the corresponding biological half-time was 13 times longer than control values. Additionally, the degree of drug retention was inversely related to blood flow, with retention increasing as blood flow decreased. The results have possible applications to the use of biodegradable microspheres in the intraarterial delivery of chemotherapeutic agents to solid tumors.     

Ethiodized oil uptake does not predict doxorubicin drug delivery after chemoembolization in VX2 liver tumors

PurposeTo investigate the accuracy of ethiodized oil as an imaging marker of chemotherapy drug delivery after liver tumor chemoembolization in an animal model of hepatocellular carcinoma.Materials and MethodsEleven VX2 liver tumors (mean diameter, 1.9 cm ± 0.4) in six New Zealand White rabbits were treated with chemoembolization using ethiodized oil and doxorubicin emulsion, followed by immediate euthanasia. Postprocedure noncontrast computed tomography (CT) was used to evaluate intratumoral ethiodized oil distribution and calculate iodine content within four peripheral tumor quadrants and the tumor core at a central tumor slice (N = 55 total tumor sections). Liquid chromatography/tandem mass spectrometry (LC-MS/MS) was then used to directly measure doxorubicin concentration in the same tissue sections. Statistical correlation was performed between tissue iodine content and doxorubicin concentration by using linear regression.ResultsChemoembolization was successfully performed in all tumors via the left or proper hepatic artery. A mean of 0.9 mL ± 0.6 ethiodized oil and 1.8 mg ± 1.2 doxorubicin were injected. CT-calculated tissue iodine content averaged 335 mg/mL ± 218. Corresponding LC-MS/MS analysis yielded a mean doxorubicin concentration of 15.8 μg/mL ± 14.3 in each sample. Although iodine content (391 mg/mL vs 112 mg/mL; P = .000) and doxorubicin concentration (18.0 μg/mL vs 7.2 μg/mL; P = .023) were significantly greater along peripheral tumor sections compared with the tumor core, no significant predictable correlation was evident between these measures (R² = 0.0099).ConclusionsTissue ethiodized oil content is a poor quantitative predictor of local doxorubicin concentration after liver tumor chemoembolization. Future studies should aim to identify a better imaging marker for chemoembolization drug delivery.     

Evaluation of different calibrated spherical polyvinyl alcohol microspheres in transcatheter arterial chemoembolization: VX2 tumor model in rabbit liver

PURPOSE: To assess whether porosity and compressibility of calibrated spherical polyvinyl alcohol (PVA) microspheres affect doxorubicin plasma and tumor concentrations after transcatheter arterial chemoembolization (TACE) in a VX2 rabbit model. MATERIALS AND METHODS: Fifteen rabbits were divided into three groups of five rabbits each. Three different types of calibrated spherical PVA microspheres with variable levels of porosity and compressibility were blindly evaluated. TACE was performed by injecting a mixture of doxorubicin (5 mg) and iodized oil (0.5 mL) followed by injection of the embolic material (0.3-0.5 mL). Plasma concentrations of doxorubicin and doxorubicinol were analyzed 20, 40, 60, and 120 minutes and 2 days after TACE, and liver tissue and tumor doxorubicin concentrations were measured 2 days after TACE. RESULTS: All calibrated spherical PVA microspheres showed similar patterns of plasma doxorubicin and doxorubicinol release and tumor concentration of doxorubicin. There were no significant differences of drug levels in either plasma or tumor in each group (P > .05). CONCLUSIONS: After TACE in a rabbit model of liver cancer, testing of three different types of spherical PVA microspheres with varying degrees of porosity and compressibility showed no significant differences in the plasma doxorubicin release pattern and tumor doxorubicin uptake.     

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.     

Embolization of high flow arteriovenous malformations: experience with use of superabsorbent polymer microspheres

PURPOSE: To determine efficacy, safety, and requirements for adjunctive embolization or surgery in the treatment of symptomatic arteriovenous malformations (AVMs) with superabsorbent polymer microsphere (SAP-MS) particles. MATERIALS AND METHODS: SAP-MS particles (sodium acrylate and vinyl alcohol copolymer) are nonbiodegradable spheres with a precisely calibrated diameter. SAP-MS particles swell by absorbing fluids and become soft and deformable. Twenty-five patients (16 men, nine women; mean age, 32 y; range 12-66 y) with symptomatic facial (n = 5), upper- (n = 8) and lower- (n = 12) extremity AVMs were treated primarily (n = 23) or preoperatively (n = 2) by transarterial embolization (TAE) treatment with use of SAP-MS particles. Direct puncture embolization (DPE; n = 4) and/or surgical intervention (n = 5; ie, skin graft, resection, or amputation) were required. Surgical specimens from the resected (n = 2) and the amputated (n = 2) patients were evaluated histologically. Follow-up study, including clinical findings and imaging studies, was performed at intervals ranging from 3 months to 1 year. Clinical outcome was evaluated retrospectively, depending on the subjective improvement of symptoms and signs, according to the medical records. RESULTS: Seventy-two TAEs (range, 1-11; mean, 2.8) and 12 DPEs (range, 1-3; mean, 2.4) were performed during the mean follow-up period of 38 months (range, 7-110 mo). Twenty patients (80%) experienced symptom improvement by embolotherapy alone (n = 17) or in combination with surgery (n = 3). One lip and two finger AVMs were totally removed by surgical excision or amputation after TAE treatment. In diffuse upper- (n = 1) and lower- (n = 1) extremity AVMs, the symptoms were uncontrolled. No nerve injury or skin necrosis was observed after TAE treatment with SAP-MS particles. Mucosal necrosis was induced by DPE with ethanol in one patient. Histologically, SAP-MS particles penetrated intralesional vessels and conformed to the vessel lumen, resulting in tight vessel occlusion. Minimal perivascular reaction was observed. CONCLUSION: SAP-MS particles were used safely in TAE treatment of AVM. TAE treatment with use of SAP-MS particles was suitable for certain symptomatic AVMs, but diffuse AVMs remain a challenge and a combination of alternative methods will be necessary for further strategy.     

Optimization of doxorubicin loading for superabsorbent polymer microspheres: in vitro analysis

Purpose  

This study was designed to establish the ability of super-absorbent polymer microspheres (SAP) to actively uptake doxorubicin and to establish the proof of principle of SAP’s ability to phase transfer doxorubicin onto the polymer matrix and to elute into buffer with a loading method that optimizes physical handling and elution characteristics.     

Transcatheter arterial chemoembolization with paclitaxel-lipiodol solution in rabbit VX2 liver tumor

PURPOSE: To evaluate the antitumor effects of transcatheter arterial chemoembolization (TACE) with a solution of an anticancer drug (Paclitaxel; Bristol-Myers Squibb, Princeton, NJ) and iodized oil (Lipiodol; Laboratoire Gurerbet, Aulnay-Sous-Bois, France) (hereafter, the solution), as well as intratumor concentration and hepatotoxicity, in experimentally induced liver tumor. MATERIALS AND METHODS: VX2 carcinoma was grown in livers of 30 rabbits. In 18 rabbits, TACE was performed with the high-dose solution (4 mg anticancer drug and 0.4 mL iodized oil, n = 6), the low-dose solution (1 mg anticancer drug and 0.4 mL iodized oil, n = 6), or iodized oil alone (0.4 mL, n = 6) in a control group. One week later, the growth ratio and residual viable proportion of the tumors were calculated on the basis of findings at spiral computed tomography and histopathologic examination. Hepatic and hematologic toxicities were evaluated by means of biochemical analysis. Differences between the three groups were statistically assessed with the Kruskal-Wallace and Mann-Whitney U tests. The remaining 12 animals were treated with the high-dose solution and serially sacrificed for clarification of chronologic change of concentration of the anticancer drug in liver tissues. RESULTS: Growth ratios and residual viable proportions of the tumors were significantly lower in the solution groups (high dose, 3.3% +/- 6.2 [mean +/- SD] and 2.8% +/- 3.6, respectively; low dose, 18.7% +/- 7.4 and 12.7% +/- 6.1, respectively) than in the control group (68.3% +/- 12.7 and 31.1% +/- 8.8, respectively) (P <.05). Hepatotoxicity was transient in all but one rabbit, which died 2 days after TACE with substantial biochemical changes. The anticancer drug accumulated in tumor where the concentration peaked at day 3 and returned to levels comparable to those for normal hepatic parenchyma at 7 days after TACE. CONCLUSION: TACE with the Paclitaxel-Lipiodol solution has dose-dependent antitumor effects without major toxicities in VX2 liver tumor.     

Pharmacokinetic study of conventional sorafenib chemoembolization in a rabbit VX2 liver tumor model

PURPOSE

Use of oral sorafenib, an antiangiogenic chemotherapeutic agent for hepatocellular carcinoma (HCC), is limited by an unfavorable side effect profile. Transarterial chemoembolization (TACE) employs targeted intravascular drug administration, and has potential as a novel sorafenib delivery method to increase tumoral concentrations and reduce systemic levels. This study aimed to discern the pharmacokinetics of sorafenib TACE in a rabbit VX2 liver tumor model.

METHODS

A 3 mg/kg dose of sorafenib ethiodized oil emulsion was delivered via an arterial catheter to VX2 liver tumors in seven New Zealand white rabbits. Following TACE, serum sorafenib levels were measured at days 0, 1, 2, 3, 7, 10, and 14 until the time of sacrifice, after which rabbit livers were harvested for analysis of sorafenib concentrations within treated tumors and normal liver. Liquid chromatography tandem mass spectrometry was used for drug quantification.

RESULTS

Sorafenib uptake within liver tumor and nontumorous liver tissue peaked at mean 3.53 and 0.75 μg/mL, respectively, immediately post-procedure (5:1 tumor to normal tissue drug uptake ratio), before decreasing with a 10–18 hour half-life. Serum sorafenib levels peaked immediately after TACE at a mean value of 58.58 μg/mL before normalizing with a 5.2-hour half-life, suggesting early drug washout from liver into the systemic circulation. Hepatic lab parameters showed transient increase 24 hours post-TACE with subsequent resolution.

CONCLUSION

While targeted transarterial delivery of sorafenib ethiodized oil emulsion shows preferential tumor uptake compared to normal liver, systemic washout occurs with a short half-life, resulting in high circulating drug levels.Sorafenib (Nexavar, Bayer Pharmaceuticals) is an antiangiogenic chemotherapeutic multikinase inhibitor that targets vascular endothelial growth factor (VEGF) receptor (1). This drug is approved by the United States Food and Drug Administration (FDA) as an oral agent for treatment of surgically unresectable primary liver cancer (hepatocellular carcinoma, HCC), and is associated with prolongation in tumor time-to-progression and patient overall survival in phase 3 clinical trials (2, 3). The practical utility of sorafenib is tempered, however, by a high incidence of clinically significant side effects related to systemic distribution, including hand-foot syndrome, nausea, diarrhea, and fatigue, which are frequently cited as reasons for patient noncompliance and drug dose limitation (4); serious adverse events occur in 48%–52% of those patients taking sorafenib (2, 3).Transarterial chemoembolization (TACE) is a widely performed and recognized locoregional drug delivery methodology. During TACE, chemotherapy is administered to solid tumors in a targeted fashion via arterially placed catheters (5). This procedure, which has shown survival benefit in the treatment of HCC (6, 7), exploits the hepatic arterial perfusion of liver cancer to administer targeted therapy with cytotoxic chemotherapeutic agents, and also aims to devascularize neoplastic tissue by occluding feeding arteries. Conventional TACE consists of a mixture of chemotherapeutic agents and embolic ethiodized oil (5, 8), which slows blood flow through the tumor and sequesters chemotherapy medications to achieve high localized intratumoral drug concentration while limiting systemic release. In contrast to standard oral administration, targeted transarterial delivery of sorafenib has the potential to deliver high localized drug concentrations directly to liver tumors while theoretically reducing extrahepatic levels and diminishing adverse systemic effects of the drug.A previous investigation aimed at translating the high local drug concentrations and low systemic drug levels conferred by targeted TACE toward intrahepatic delivery of sorafenib has demonstrated the feasibility of transcatheter intra-arterial delivery of lipid-emulsified sorafenib in rabbit livers (9). While this method of sorafenib delivery produced high intrahepatic drug concentrations, this study did not elucidate the pharmacokinetics of conventional sorafenib TACE in terms of comparing intra- and extrahepatic drug levels over time. An understanding of the dynamic local and circulating concentrations of sorafenib after transarterial delivery is necessary to provide a foundation on which to base future studies aimed at correlating plasma drug levels with the incidence of side effects and determining the maximum tolerated dose of transarterially delivered sorafenib. The current investigation was thus conducted to determine the pharmacokinetics of conventional sorafenib TACE and to test the hypothesis that sorafenib TACE yields high tissue levels of sorafenib while minimizing systemic release through temporal assessment of liver tissue and circulating drug levels.     

经动脉灌注5-FU缓释微球治疗兔VX2肝肿瘤

目的 研究5-FU缓释微球经胃十二指肠动脉灌注对兔VX2肝肿瘤的治疗作用.方法 将成功接种肝VX2肿瘤的模型兔随机分成4组,每组10只,用显微外科手术临时阻断肝总动脉血流,经胃十二指肠动脉插管至肝固有动脉起始部给药行介入治疗,术毕结扎胃十二指肠动脉.A组(生理盐水对照组),注射生理盐水0.5～1 ml;B组(碘佛醇对照组)注射碘佛醇0.5～1 ml;C组为碘油组(疗效对比组),注射超液化碘油0.5～1.0ml;D组为5-FU缓释微球组,注射5-FU缓释微球10mg和碘佛醇1 ml混合溶液.4组实验动物于治疗1周后观察肿瘤生长情况、坏死程度.并采用原位末端标记法(TUNEL)检测肿瘤细胞凋亡指数(AI).结果 治疗1周后5-FU缓释微球组肿瘤生长受到抑制,肿瘤生长率低于生理盐水对照组和碘佛醇对照组(P<0.05),与碘油组差异无统计学意义(P>0.05).4组肿瘤均有不同程度坏死,5-FU缓释微球组和碘油组肿瘤坏死率明显高于另两组(P<0.05).生理盐水对照组、碘佛醇对照组和5-FU缓释微球组肿瘤细胞凋亡指数分别为1.69±0.18、1.75±0.27和8.03±0.63,5-FU缓释微球组与各对照组相比差异有统计学意义(P<0.05).结论 5-FU缓释微球经动脉灌注可抑制肝肿瘤生长,诱导肿瘤细胞凋亡,促进肿瘤坏死,是有效的化疗栓塞剂.     

In vivo diffusion-weighted imaging of liver tumor necrosis in the VX2 rabbit model at 1.5 Tesla

OBJECTIVES: We sought to demonstrate the feasibility of using single-shot spin-echo echo-planar imaging for imaging liver tumor necrosis in the in vivo VX2 rabbit model at 1.5 T. MATERIALS AND METHODS: VX2 liver tumors were grown in 4 rabbits. Diffusion-weighted images (DWIs) were acquired during breath-hold using twice refocused SE-EPI (b = 0, 700, 1400 seconds/mm). Anatomic images for tumor size measurements were acquired using T2W TSE. Rabbits were euthanized for subsequent necropsy. Viable and necrotic tumor tissue ADC measurements were performed with reference to hematoxylin and eosin pathology. RESULTS: A total of 8 tumors were grown with diameters ranging from 1.2 to 5.3 cm. Viable and necrotic tumor compartments were clearly differentiated. Apparent diffusion coefficient in necrotic tumor cores, 1.26 +/- 0.11 x 10 mm/s, were significantly greater than those in surrounding viable tumor tissues, 0.74 +/- 0.06 x 10 mm/s (mean +/- SD, P < 0.05). CONCLUSIONS: In vivo DWI of liver tumor necrosis in the VX2 rabbit model is feasible using a 1.5 T clinical magnetic resonance imaging scanner. DWI may permit longitudinal assessment of liver tumor therapies in both preclinical and clinical studies.     

3.0 T MR扩散加权成像评价兔肝VX2瘤射频消融治疗的实验研究

目的 探讨3.0 T MR DWI评价兔肝VX2瘤射频消融治疗疗效的价值.方法 新西兰大白兔22只.20只用于建立VX2瘤模型,2只健康正常兔用于行正常肝射频消融术对照.于VX2瘤种植后14～21 d(平均17 d),对符合实验条件瘤兔(病灶位于肝实质内,最大直径≤3 cm,坏死病灶直径≤整个病灶直径的1/2)行3.0 T常规MRI和功能DWI.对瘤兔及对照组正常兔行射频消融治疗,射频消融术后7～10 d(平均8 d)行3.0 T常规MRI及DWI.所有射频消融治疗兔行MR检查后均行病理检查.测量兔肝VX2瘤、正常兔肝射频消融治疗前后ADC值,分析兔肝VX2瘤射频消融治疗前后3.0 T MR常规成像、ADC值特征,并与病理对照.同一b值射频消融治疗后不同组织间ADC值比较采用重复测量资料方差分析.结果 20只实验组兔肝VX2瘤模型均建立成功,1例肿瘤突出于肝表面、1例肿瘤病灶出现明显坏死未纳入实验.所有18个瘤灶及2例正常兔肝射频消融均成功.兔VX2瘤T1WI序列表现为低或等信号,T2WI为高信号.肝VX2瘤兔射频消融治疗后7～10 d,射频消融病灶T1WI序列表现为低或稍高信号,T2WI为混杂信号.T2WI序列周边环形稍高信号为肉芽组织,增强扫描明显强化,T2WI序列低、中等信号为凝固性坏死.坏死组织在DWI图上为低信号,活性肿瘤组织位于病灶周边,呈结节状,在T2WI、DWI图上为等或稍高信号.肿瘤标本为灰白色,部分肿瘤组织间夹杂增生血管、少许肉芽组织.b值为600 s/mm2时,射频消融治疗后活性肿瘤组织(9只)、坏死组织(18只)、肉芽组织(18只)、正常组织(18只)ADC值分别为:(1.227±0.140)×10-3、(0.702±0.050)×10-3、(1.918±0.124)×10-3、(1.739±0.044)×10-3mm2/s,各组间ADC值差异具有统计学意义(P＜0.01).b值分别为200、400、600、800、1000 s/mm2时治疗后坏死组织、活性残留或复发肿瘤组织、肉芽组织、正常肝组织间ADC值差异具有统计学意义(P＜0.01).结论 兔VX2瘤模型适合3.0 T MR评价射频消融治疗疗效的动物实验研究,对射频消融治疗基础及临床应用研究具有重要价值.     

Embolic effects of superabsorbent polymer microspheres in rabbit renal model: comparison with tris-acryl gelatin microspheres and polyvinyl alcohol

PURPOSE: We have developed a spherical embolic agent, superabsorbent polymer microspheres (SAP-MS). The aim of this study was to examine the embolic effects of SAP-MS in comparison with polyvinyl alcohol (PVA) particles and tris-acryl gelatin microsphere (Embosphere Microsphere; EM) in a rabbit renal model. MATERIALS AND METHODS: The right kidneys of nine rabbits were embolized with the given agents: PVA (180-300 microm) (n=3), EM (100-300 microm) (n=3), and SAP-MS (106-150 microm) (n=3). The embolized kidneys were evaluated by angiography and histology after one week. RESULTS: Renal artery occlusion and prominent coagulative necrosis were confirmed regardless of agent. PVA aggregated in the proximal vessels with tiny fragments migrating into glomeruli. Both EM and SAP-MS traveled distally up to the interlobular artery level, and a single particle achieved cross-sectional vessel occlusion. SAP-MS was markedly swollen, deformed, and conformed to the vessel lumen compared with the constantly spherical EM. Mild perivascular reaction was seen with both microspheres. CONCLUSION: SAP-MS resulted in targeted end-organ infarction in the rabbit renal model and showed different mechanical properties from other agents.     

介入导入三氧化二砷微球对VX2兔肝肿瘤模型的治疗作用

目的 观察介入导入三氧化二砷(As2O3)微球对VX2兔肝肿瘤模型的治疗作用.方法 新西兰大白兔32只,体重2.3～2.8 kg,制作VX2兔肝肿瘤模型并随机分成4组,每组8只,均经右侧股动脉插管至肝动脉,向肿瘤供血动脉给药:a组动脉灌注组:As2O3 3 mg/kg 生理盐水10 ml;b组As2O3微球栓塞组:注入As2O3 PLGA微球3 mg/kg;c组空白微球栓塞组:注入PLGA微球3 mg/kg;d组为对照组:经肝动脉注入生理盐水10ml.兔肝肿瘤模型制作后14 d行肝螺旋CT双期动态扫描,根据螺旋CT扫描获得肝内肿瘤影像,测量肿瘤大小,次日行介入治疗,术后第21天处死实验兔后,取出肝脏,测量瘤体大小;肿瘤组织4%甲醛固定,多点取材,HE染色,显微镜检.结果 实验兔介入操作均获成功,且均存活.肿瘤平扫呈低密度,与周围正常肝实质分界欠清.增强后动脉期肿瘤强化明显,坏死组织无强化,呈不均匀高密度,肿瘤与周围肝实质分界清楚.门脉期肿瘤呈不均匀低密度,而周围正常肝实质强化明显,术后CT随访d组和a组肿瘤明显增大,中央呈低密度;c组肿瘤有轻度强化,b组肿瘤体积小,呈低密度,边界清楚,强化不明显.各组肿瘤体积术前无统计学差异,术后标本体积测量显示As2O3微球栓塞组瘤体最小,a、b、c组与d组间有显著统计学差异(P＜0.05);b组与c组、a组间有显著统计学差异(P＜0.05).病理检查显示a组和d组肿瘤体积大,呈鱼肉样,质地脆,坏死区位于肿瘤中心区域,白色豆渣样,肿瘤血管丰富;显微镜下肿瘤细胞丰富,巢团状排列,纤维样组织少与正常肝组织分界不清,呈浸润性生长.b组肿瘤体积小,坏死明显,坏死区边缘纤维组织丰富,在纤维组织内可见残存瘤巢.在纤维组织外围见到肝细胞空泡变性,呈片状分布.结论 As2O3 PLGA微球对VX2兔肝肿瘤有良好的化疗栓塞效果,使用安全.     

当归对兔VX2肝癌放疗联合介入治疗后肝纤维化的影响

目的 观察当归对兔VX2肝癌放疗(RT)联合动脉化疗栓塞(TACE)术后肝纤维化的预防作用,并探讨其预防肝纤维化的作用机制。方法 将50只新西兰白兔随机表法分为对照组(n=10)、模型组(n=10)和预防组(n=30)。模型组:兔VX2肝癌种植2周后经胃十二指肠动脉注入平阳霉素1 mg+碘油0.2 ml, 1周后单次行左肝照射20 Gy;预防组:荷VX2肝癌兔在行RT联合TACE(剂量同模型组)术时经耳静脉注射当归注射液,根据当归注射液量的不同进一步分为小剂量组(4 ml/kg)、中剂量组(6 ml/kg)和大剂量组(8 ml/kg),每周2次,共4周;对照组:不进行VX2肝癌种植,经胃十二指肠动脉注入生理盐水2 ml。于RT联合TACE术后第6周末检测HA、LN、PCⅢ和CIV,并进行肝组织HE、VG和TGF-β1免疫组织化学染色。结果 模型组的肝纤维化病理分期主要处于肝纤维化Ⅱ期和Ⅲ期,预防组的肝纤维化分期主要处于肝纤维化Ⅰ期,各组之间分期差异有统计学意义,肝纤维化分期与当归治疗相关(r=0.7631,P<0.01);模型组血清HA、LN、PCⅢ和CIV明显高于对照组(P<0.01),预防组与模型组相比明显降低(P<0.05);模型组肝组织TGF-β1表达增强,预防组TGF-β1表达较模型组明显减少,且不同剂量当归预防组之间存在量效关系(r=0.4427,P<0.01)。结论 当归对兔VX2肝癌RT联合TACE术后肝纤维化有预防作用,TGF-β1参与其调控机制。     

介入导人三氧化二砷微球对VX2兔肝肿瘤模型的治疗作用

目的观察介入导入三氧化二砷(As_2O_3)微球对VX2兔肝肿瘤模型的治疗作用。方法新西兰大白兔32只,体重2．3～2．8 kg,制作VX2兔肝肿瘤模型并随机分成4组,每组8只,均经右侧股动脉插管至肝动脉,向肿瘤供血动脉给药:a组动脉灌注组:As_2O_3 3 mg/kg+生理盐水10 ml;b组As_2O_3微球栓塞组:注入As_2O_3 PLGA微球3 mg/kg;c组空白微球栓塞组:注入PLGA微球3 mg/kg;d组为对照组:经肝动脉注入生理盐水10 ml。兔肝肿瘤模型制作后14 d行肝螺旋CT双期动态扫描,根据螺旋CT扫描获得肝内肿瘤影像,测量肿瘤大小,次日行介入治疗,术后第21天处死实验兔后,取出肝脏,测量瘤体大小;肿瘤组织4%甲醛固定,多点取材,HE染色,显微镜检。结果实验兔介入操作均获成功,且均存活。肿瘤平扫呈低密度,与周围正常肝实质分界欠清。增强后动脉期肿瘤强化明显,坏死组织无强化,呈不均匀高密度,肿瘤与周围肝实质分界清楚。门脉期肿瘤呈不均匀低密度,而周围正常肝实质强化明显,术后CT随访d组和a组肿瘤明显增大,中央呈低密度;c组肿瘤有轻度强化,b组肿瘤体积小,呈低密度,边界清楚,强化不明显。各组肿瘤体积术前无统计学差异,术后标本体积测量显示As_2O_3微球栓塞组瘤体最小,a、b、c组与d组间有显著统计学差异(P＜0．05);b组与c组、a组间有显著统计学差异(P＜0．05)。病理检查显示a组和d组肿瘤体积大,呈鱼肉样,质地脆,坏死区位于肿瘤中心区域,白色豆渣样,肿瘤血管丰富;显微镜下肿瘤细胞丰富,巢团状排列,纤维样组织少与正常肝组织分界不清,呈浸润性生长。b组肿瘤体积小,坏死明显,坏死区边缘纤维组织丰富,在纤维组织内可见残存瘤巢。在纤维组织外围见到肝细胞空泡变性,呈片状分布。结论As_2O_3 PLGA微球对VX2兔肝肿瘤有良好的化疗栓塞效果,使用安全。