RESUMEN
PURPOSE: To identify specific Pluronic triblock copolymer structural properties which are critical to its function as a sensitiser in hyperthermia treatment of experimental colorectal adenocarcinoma. MATERIALS AND METHODS: DHD/K12/TRb rat colorectal adenocarcinoma cells were exposed to Pluronics, a family of triblock copolymers with the general structure EO(x)-PO(y)-EO(x) (EO: ethylene oxide, and PO: propylene oxide), at a range of molecular weights (Mw) and EO:PO:EO sub-unit lengths and then submitted to sublethal heat (43°C) treatment. Outcomes indicating Pluronic performance as a thermal sensitiser were correlated with its structural properties; lead candidates were determined accordingly. Finally, one of the lead candidates, Pluronic L61, a 2000 Da copolymer, was used to assess sensitising functionality in vivo in a subcutaneous rat model of colorectal carcinoma. RESULTS: Pluronics with 1100 ≤ Mw ≤ 3200 Da and hydrophilic lipophilic balance (HLB) between 1-8 demonstrated the highest thermosensitising ability. Pluronics L31, L61, L62, L10 and L64 were found to be among the most effective copolymers for hyperthermia sensitisation under tested conditions. Most encouraging, L61 in synergy with hyperthermia significantly reduced tumour growth progression in vivo compared to tumours treated with hyperthermia alone. CONCLUSIONS: Pluronic copolymer structure properties including, Mw, HLB and PO length are essential to its hyperthermia sensitising function.
Asunto(s)
Adenocarcinoma/terapia , Neoplasias Colorrectales/terapia , Hipertermia Inducida/métodos , Poloxámero/química , Animales , Apoptosis/efectos de los fármacos , Ablación por Catéter , Línea Celular Tumoral , Interacciones Hidrofóbicas e Hidrofílicas , Masculino , Peso Molecular , Poloxámero/uso terapéutico , RatasRESUMEN
PURPOSE: The goal of this study was to evaluate the relationship between previously demonstrated thermosensitising effects of the block copolymer, Pluronic, and heat shock protein 70 (Hsp70) expression in an experimental colorectal cancer model in vitro and in vivo. MATERIALS AND METHODS: Rat colorectal carcinoma cells were treated with low-grade hyperthermia (43°C) alone or in combination with Pluronics L10 (3 mg/mL), L61 (0.3 mg/mL), or L64 (0.5 mg/mL) for 20 min. Adinosine triphosphate (ATP) levels and cell viability were determined using standard assays. Hsp70 expression was quantified by western blot for cells treated with L10, L61, and L64 at doses specified above and Pluronic P85 (10 mg/mL) alone and in combination with heat. BDIX rats with flank tumours were used to study the effect of L61 and hyperthermia on Hsp70 expression in vivo. RESULTS: In vitro, treatment with L10, L61, and L64 plus low-grade hyperthermia lead to depletion of ATP levels to between 8 and 66% of untreated control after 24 h. Maximum expression of Hsp70 was observed at 9 h following hyperthermia alone. The combination of low-grade hyperthermia and Pluronic treatment reduced Hsp70 expression for up to 6 hours, and L10 appeared to completely inhibit the Hsp70 expression. In vivo, Hsp70 expression was increased 5 h after hyperthermia in BDIX rat tumour models and no Hsp70 expression was observed in L61 pre-treated and control groups. CONCLUSION: Pluronic effectively improves hyperthermic and low-grade hyperthermic treatment in part due to reduction of Hsp70 expression.
Asunto(s)
Adenocarcinoma/metabolismo , Neoplasias Colorrectales/metabolismo , Proteínas HSP70 de Choque Térmico/biosíntesis , Poloxámero/farmacología , Animales , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Proteínas HSP70 de Choque Térmico/antagonistas & inhibidores , Hipertermia Inducida , RatasRESUMEN
The advent of microbubble contrast agents has enhanced the capabilities of ultrasound as a medical imaging modality and stimulated innovative strategies for ultrasound-mediated drug and gene delivery. While the utilization of microbubbles as carrier vehicles has shown encouraging results in cancer therapy, their applicability has been limited by a large size which typically confines them to the vasculature. To enhance their multifunctional contrast and delivery capacity, it is critical to reduce bubble size to the nanometer range without reducing echogenicity. In this work, we present a novel strategy for formulation of nanosized, echogenic lipid bubbles by incorporating the surfactant Pluronic, a triblock copolymer of ethylene oxide copropylene oxide coethylene oxide into the formulation. Five Pluronics (L31, L61, L81, L64 and P85) with a range of molecular weights (M(w): 1100 to 4600 Da) were incorporated into the lipid shell either before or after lipid film hydration and before addition of perfluorocarbon gas. Results demonstrate that Pluronic-lipid interactions lead to a significantly reduced bubble size. Among the tested formulations, bubbles made with Pluronic L61 were the smallest with a mean hydrodynamic diameter of 207.9 +/- 74.7 nm compared to the 880.9 +/- 127.6 nm control bubbles. Pluronic L81 also significantly reduced bubble size to 406.8 +/- 21.0 nm. We conclude that Pluronic is effective in lipid bubble size control, and Pluronic M(w), hydrophilic-lipophilic balance (HLB), and Pluronic/lipid ratio are critical determinants of the bubble size. Most importantly, our results have shown that although the bubbles are nanosized, their stability and in vitro and in vivo echogenicity are not compromised. The resulting nanobubbles may be better suited for contrast enhanced tumor imaging and subsequent therapeutic delivery.
Asunto(s)
Medios de Contraste , Lípidos , Microburbujas , Poloxámero , Ultrasonografía/métodos , Animales , Neoplasias Colorrectales/diagnóstico por imagen , Medios de Contraste/química , Portadores de Fármacos , Estabilidad de Medicamentos , Femenino , Interacciones Hidrofóbicas e Hidrofílicas , Lípidos/química , Tamaño de la Partícula , Poloxámero/química , Ratas , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Pluronic block copolymers have been shown to sensitize cancer cells resulting in an increased activity of antineoplastic agents. In the current study we examined a new application of Pluronic bioactivity in potentiating hyperthermia-induced cancer cell injury. DHD/K12/TRb rat adenocarcinoma cells were exposed to low-grade hyperthermia at 43 degrees C with or without Pluronic P85 or Pluronic L61. A range of Pluronic doses, pre-exposure and heat exposure durations were investigated, and the test conditions were optimized. Treatment efficacy was assessed by measurement of intracellular ATP and mitochondrial dehydrogenase activity. Both P85 and L61 in synergy with heat reduced cell viability appreciably compared to either heat or Pluronic alone. Under optimal conditions, P85 (10 mg/ml, 240 mins) combined with 15 mins heat reduced intracellular ATP to 60.1 +/- 3.5% of control, while heat alone and P85 without heat caused a negligible decrease in ATP of 1.2% and 3.8%, respectively. Similarly, cells receiving 120 mins pre-exposure of L61 (0.3 mg/ml) showed reduction in intracellular ATP to 14.1 +/- 2.1% of control. Again, heat or L61 pre-exposure alone caused a minor decrease in levels of intracellular ATP (1.5% and 4.4%, respectively). Comparable results were observed when viability was assessed by mitochondrial enzyme activity. Survival studies confirmed that the loss of viability translates to a long-term reduction in proliferative activity, particularly for L61 treated cells. Based on these results, we conclude that Pluronic is effective in improving hyperthermic cancer treatment in vitro by potentiating heat-induced cytotoxicity in a concentration and time dependent manner.
Asunto(s)
Adenocarcinoma/patología , Hipertermia Inducida/métodos , Poloxámero/toxicidad , Adenosina Trifosfato/metabolismo , Animales , Supervivencia Celular/efectos de los fármacos , Cinética , Mitocondrias/efectos de los fármacos , Mitocondrias/patología , Poloxaleno/toxicidad , Ratas , Factores de TiempoRESUMEN
PURPOSE: To prospectively determine, in an animal tumor model, if the block copolymer Pluronic P85 (BASF, Shreveport, La) sensitizes cancer cells to hyperthermia and if intratumorally or intravenously administered copolymer improves the therapeutic outcome of radiofrequency (RF) ablation tumor treatment. MATERIALS AND METHODS: The effects of Pluronic P85 and mild hyperthermia in vitro were tested in DHD/K12/TRb rat colorectal carcinoma cells. Cells were incubated at 37 degrees C or 43 degrees C for 15-60 minutes with 0%, 7%, or 10% wt/wt Pluronic P85, and cell viability was assessed by using a mitochondrial enzyme assay. In vivo experiments were performed as approved by the Institutional Animal Care and Use Committee at Case Western Reserve University and according to all applicable guidelines on animal use. Bilateral subcutaneous tumors in rats were treated with either intratumoral (13 tumors) or intravenous (15 tumors) Pluronic P85 followed by ablation or with ablation alone (14 tumors) and were monitored for 14 days by using volumes estimated from caliper measurements of tumor diameter. Acute effects of Pluronic P85 on the size of ablation-induced coagulation were measured after 24 hours in additional tumors (six tumors each treated according to the protocol for the ablation-only, intratumoral injection, and intravenous injection groups). Statistical testing was performed by using linear regression analysis and two-sided t tests with a significance level of .05. RESULTS: At 43 degrees C, 7% and 10% Pluronic P85 reduced in vitro cell viability by 22% +/- 5 (standard error of the mean) (P < .001) and 28% +/- 5 (P < .001), respectively, compared with the viability of control cells. At day 14, the volume of tumors ablated after local and systemic Pluronic P85 pretreatment changed by -55% +/- 14 (P = .03) and -59% +/- 14 (P = .02), respectively, compared with an increase of 16% +/- 28 for tumors treated with ablation alone. Coagulation area at 24 hours was reduced by 44% relative to that in control tumors (P = .03) after intratumoral Pluronic P85 but was unchanged after systemic Pluronic P85. CONCLUSION: Tumor pretreatment with Pluronic P85 improved the outcome of RF ablation by decreasing the tumor volume and residual tumor in an experimental carcinoma model.
Asunto(s)
Ablación por Catéter , Neoplasias Colorrectales/terapia , Poloxaleno/farmacología , Animales , Línea Celular Tumoral , Quimioterapia Adyuvante , Neoplasias Colorrectales/patología , Terapia Combinada , Hipertermia Inducida , Inyecciones Intralesiones , Modelos Lineales , Trasplante de Neoplasias , Poloxaleno/administración & dosificación , Estudios Prospectivos , RatasRESUMEN
Pluronic, a poly(ethylene oxide)-poly(propylene oxide)-poly (ethylene oxide) block copolymer, has been shown to enhance the cytotoxic activity of anticancer drugs in various cell lines. In the current study the effect of Pluronic P85 (P85) and Pluronic L61 (L61) on the intratumoral chemotherapy of an experimental adenocarcinoma in rats was examined. A total of 120 subcutaneous tumors (4 per rat) were inoculated in 30 BDIX rats and were treated weekly for 4 weeks with intratumoral injection of carboplatin (CPt) alone or with either P85 or L61. Tumors were monitored weekly and were excised at the endpoint for histologic evaluation. The effect of Pluronic on levels of intracellular ATP was explored as a possible mechanism of sensitization. Results showed that tumors treated with low-dose CPt (2.8 mg/kg) and P85 or L61 exhibited significant reductions in tumor volume after 28 days relative to Day 0 (112.7% +/- 34.4%, n = 15; 131.3% +/- 55.6%, n = 8) compared with tumors treated with free drug (339.4% +/- 75.0%, n = 16). Control tumors treated with either P85 or L61 alone or with saline showed volume increases of 1079.4% +/- 143.6% (n = 16), 729.4% +/- 202.2% (n = 7), and 1119.2% +/- 6.1% (n = 16), respectively. Treatment with high-dose CPt (20.7 mg/kg) led to a 79.3% +/- 4.2% reduction in tumor volume, and no differences were noted with addition of P85 or L61. In vitro ATP measurements showed that 28.0 mg/kg of P85 significantly reduced levels of intracellular ATP to 44.7% +/- 1.5% of controls, whereas L61 at this concentration depleted ATP levels completely. Results confirm that Pluronic P85 and L61 act as potent sensitizers to carboplatin chemotherapy of the experimental colorectal carcinoma, leading to a significant reduction of tumor growth compared to carboplatin alone. ATP depletion is a possible mechanism for these observed differences.
Asunto(s)
Carboplatino/administración & dosificación , Neoplasias Colorrectales/tratamiento farmacológico , Poloxámero/administración & dosificación , Adenosina Trifosfato/metabolismo , Animales , Antineoplásicos/farmacología , Línea Celular Tumoral , Humanos , Metástasis de la Neoplasia , Trasplante de Neoplasias , Ratas , Tensoactivos/farmacología , Factores de TiempoRESUMEN
OBJECTIVE: The purpose of this study was to investigate whether an intralesional chemotherapy depot with or without a chemosensitizer could improve the efficacy of radiofrequency (RF) ablation in treatment of experimental carcinoma in rats. MATERIALS AND METHODS: Eighteen BD-IX rats were inoculated with bilateral subcutaneous tumors via injection of DHD/K12TRb rat colorectal carcinoma cells in suspension. Four weeks after inoculation, one tumor in each rat was treated with RF ablation at 80 degrees C for 2 minutes and the other with RF ablation followed by intralesional chemotherapy with carboplatin. The drug was administered via 2 different in situ-forming poly(D,L-lactide-coglycolide) (PLGA) depot formulations either with or without a chemosensitizer. Treatment efficacy was assessed by comparing the change in tumor diameter compared with control, percent of coagulation necrosis and a rating of treatment completeness. RESULTS: Tumors treated with ablation and carboplatin + sensitizer (n = 9) showed a diameter decrease of 49.4 +/- 24.5% at the end point relative to ablation control, while those treated with ablation and carboplatin only (n = 8) showed a 7.1 +/- 12.6% decrease. Use of sensitizer also showed increased tissue necrosis (81.9 +/- 9.7% compared with 68.7 +/- 26.7% for ablation only) and double the number of complete treatments (6/9 or 66.7%) compared with ablation control (3/9 or 33.3%). CONCLUSIONS: From these results, we conclude that intralesional administration of a carboplatin and sensitizer-loaded polymer depot after RF ablation has the potential to improve the outcome of ablation by increasing effectiveness of local adjuvant chemotherapy in preventing progression of tumor unaffected by the ablation treatment.
Asunto(s)
Carcinoma/terapia , Ablación por Catéter , Neoplasias Colorrectales/terapia , Poloxaleno/administración & dosificación , Animales , Antineoplásicos/administración & dosificación , Carboplatino/administración & dosificación , Línea Celular Tumoral , Terapia Combinada , Preparaciones de Acción Retardada/administración & dosificación , Femenino , Inyecciones Intralesiones , Masculino , Trasplante de Neoplasias , Ratas , Resultado del TratamientoRESUMEN
The objective of this study was to examine the effects of three Pluronic triblock copolymers (F127, P85, or L61) on the cytotoxicity of carboplatin to the DHB/K12/TRb rat colorectal carcinoma cell line. Studies to determine the dependence of the sensitization effect on Pluronic dose were carried out for polymer concentrations ranging from 0.0001-10% (w/w). To establish the carboplatin toxicity and its potential enhancement by Pluronic, the drug was delivered to cells in doses ranging from 0-0.5% (w/w) in the presence of Pluronic at a constant concentration. These treatment groups were compared to control groups receiving carboplatin alone. Cell cytotoxicity resulting from the treatments was determined with a mitochondrial enzyme activity assay (WST-1), while cell morphology was examined with May-Grünwald and Giemsa staining. Results indicate that the greatest enhancement of carboplatin toxicity was induced by P85, where the inhibitory concentration (IC(50)) was reduced by 50% (from 0.096 mg/mL for carboplatin alone to 0.048 mg/mL in presence of P85). L61 was toxic to the cells with or without drug (viability<3.5%), while F127 exhibited no sensitizing effect and in some cases increased the cell viability to 130% over the untreated control. The WST-1 results were confirmed by trypan blue exclusion cell counts at 0 and 24 h post treatment. Data conclusively demonstrate that Pluronic P85 is the optimal agent for increased cytotoxicity of carboplatin in this cell line and can potentially be used not only as a drug delivery scheme but also as a chemosensitizing agent in future cancer therapy.
Asunto(s)
Antineoplásicos/administración & dosificación , Carboplatino/administración & dosificación , Supervivencia Celular/efectos de los fármacos , Poloxaleno/administración & dosificación , Poloxámero/administración & dosificación , Animales , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Portadores de Fármacos , Micelas , RatasRESUMEN
In contrast to the clinically used microbubble ultrasound contrast agents, nanoscale bubbles (or nanobubbles) may potentially extravasate into tumors that exhibit more permeable vasculature, facilitating targeted molecular imaging and drug delivery. Our group recently presented a simple strategy using the non-ionic surfactant Pluronic as a size control excipient to produce nanobubbles with a mean diameter of 200 nm that exhibited stability and echogenicity on par with microbubbles. The objective of this study was to carry out an in-depth characterization of nanobubble properties as compared with Definity microbubbles, both in vitro and in vivo. Through use of a tissue-mimicking phantom, in vitro experiments measured the echogenicity of the contrast agent solutions and the contrast agent dissolution rate over time. Nanobubbles were found to be more echogenic than Definity microbubbles at three different harmonic frequencies (8, 6.2 and 3.5 MHz). Definity microbubbles also dissolved 1.67 times faster than nanobubbles. Pharmacokinetic studies were then performed in vivo in a subcutaneous human colorectal adenocarcinoma (LS174T) in mice. The peak enhancement and decay rates of contrast agents after bolus injection in the liver, kidney and tumor were analyzed. No significant differences were observed in peak enhancement between the nanobubble and Definity groups in the three tested regions (tumor, liver and kidney). However, the decay rates of nanobubbles in tumor and kidney were significantly slower than those of Definity in the first 200-s fast initial phase. There were no significant differences in the decay rates in the liver in the initial phase or in three regions of interest in the terminal phase. Our results suggest that the stability and acoustic properties of the new nanobubble contrast agents are superior to those of the clinically used Definity microbubbles. The slower washout of nanobubbles in tumors suggests potential entrapment of the bubbles within the tumor parenchyma.
Asunto(s)
Fluorocarburos/farmacocinética , Nanopartículas , Poloxámero/farmacocinética , Ultrasonografía/métodos , Animales , Fluorocarburos/química , Ensayo de Materiales , Tasa de Depuración Metabólica , Ratones , Ratones Desnudos , Nanopartículas/química , Especificidad de Órganos , Fantasmas de Imagen , Poloxámero/química , Distribución Tisular , Ultrasonografía/instrumentaciónRESUMEN
Current strategies for tumor-induced sentinel lymph node detection and metastasis therapy have limitations. In this work, we co-encapsulated iron oxide nanoparticles and chemotherapeutic drug into poly(lactic-co-glycolic acid) (PLGA) microbubbles to form multifunctional polymer microbubbles (MPMBs) for both tumor lymph node imaging and therapy. Fe(3)O(4) nanoparticles and doxorubicin (DOX) co-encapsulated PLGA microbubbles were prepared and filled with perfluorocarbon gas. Enhancement of ultrasound (US)/magnetic resonance (MR) imaging and US triggered drug delivery were evaluated both in vitro and in vivo. The MPMBs exhibited characters like narrow size distribution and smooth surface with a mean diameter of 868.0 ± 68.73 nm. In addition, varying the concentration of Fe(3)O(4) nanoparticles in the bubbles did not significantly influence the DOX encapsulation efficiency or drug loading efficiency. Our in vitro results demonstrated that these MPMBs could enhance both US and MR imaging which was further validated in vivo showing that these MPMBs enhanced tumor lymph nodes signals. The anti-tumor effect of MPMBs mediated chemotherapy was assessed in vivo using end markers like tumor proliferation index, micro blood vessel density and micro lymphatic vessel density, which were shown consistently the lowest after the MPMBs plus sonication treatment compared to controls. In line with these findings, the tumor cell apoptotic index was found the largest after the MPMBs plus sonication treatment. In conclusion, we have successfully developed a doxorubicin loaded superparamagnetic PLGA-Iron Oxide multifunctional theranostic agent for dual-mode US/MR Imaging of lymph node, and for low frequency US triggered therapy of metastasis in lymph nodes, which might provide a strategy for the imaging and chemotherapy of primary tumor and their metastases.
Asunto(s)
Doxorrubicina/farmacología , Ácido Láctico/farmacología , Ganglios Linfáticos/efectos de los fármacos , Imagen por Resonancia Magnética/métodos , Microburbujas , Ácido Poliglicólico/farmacología , Animales , Línea Celular Tumoral , Medios de Contraste , Sistemas de Liberación de Medicamentos , Ganglios Linfáticos/patología , Metástasis Linfática , Nanopartículas/química , Copolímero de Ácido Poliláctico-Ácido Poliglicólico , Conejos , UltrasonidoRESUMEN
Lymph node (LN) examination plays a critical role in the staging and treatment of several kinds of cancer such as lesions of the breast. However current strategies have limitations. This study aimed to develop a novel imaging agent, a polymeric ultrasonographic contrast agent carrying Sudan black (SB), for ultrasonographic imaging of the regional LNs before surgery and to directly localize the LNs during surgery. The poly(lactide-co-glycolide) (PLGA) ultrasonographic microbubbles carrying Sudan black B (SB) (SB-PLGA microbubbles) were prepared by the double emulsion method. The SB-PLGA microbubbles had a diameter of 1.5 ± 0.5 µm and the SB encapsulation efficiency was (86.2 ± 1.56%). Results from MTT assays suggested that these bubbles have little cytotoxicity to mouse macrophages after incubation. Confocal laser scanning microscopy showed that the PLGA microbubbles carrying the fluorescent dye rhodamine 6G were taken up by macrophages after 2-hour incubation. In addition, these SB-PLGA microbubbles were able to enhance ultrasonographic contrast of 12 popliteal LNs of 6 rabbits. Furthermore, the LNs were easily identifiable by the naked eye during surgery because of the blue color of the SB-PLGA microbubbles inside the LNs. By cryosectioning and hematoxylin and eosin (H&E) staining of LN tissue, our results showed that these SB-PLGA microbubbles were internalized inside the macrophages of the LNs. To conclude, the SB-PLGA microbubbles could be a suitable imaging agent for preoperative and intraoperative localization of LNs as well as for a preoperative ultrasonographically guided core needle biopsy of suspicious sentinel lymph nodes (SLNs) in cancer patients, hence enhancing treatment outcome.
Asunto(s)
Compuestos Azo/administración & dosificación , Ácido Láctico/administración & dosificación , Ganglios Linfáticos/patología , Ácido Poliglicólico/administración & dosificación , Biopsia del Ganglio Linfático Centinela/métodos , Animales , Compuestos Azo/efectos adversos , Compuestos Azo/química , Compuestos Azo/farmacocinética , Células Cultivadas , Medios de Contraste/administración & dosificación , Medios de Contraste/efectos adversos , Medios de Contraste/química , Medios de Contraste/farmacocinética , Portadores de Fármacos , Periodo Intraoperatorio , Ácido Láctico/efectos adversos , Ácido Láctico/química , Ácido Láctico/farmacocinética , Ganglios Linfáticos/efectos de los fármacos , Ganglios Linfáticos/metabolismo , Metástasis Linfática/diagnóstico por imagen , Metástasis Linfática/patología , Ratones , Microburbujas , Naftalenos , Ácido Poliglicólico/efectos adversos , Ácido Poliglicólico/química , Ácido Poliglicólico/farmacocinética , Copolímero de Ácido Poliláctico-Ácido Poliglicólico , Periodo Preoperatorio , Conejos , Biopsia del Ganglio Linfático Centinela/instrumentación , Ultrasonografía Intervencional/instrumentación , Ultrasonografía Intervencional/métodosRESUMEN
Organic/inorganic, hybrid, multifunctional, material-based platforms combine the merits of diverse functionalities of inorganic nanoparticles and the excellent biocompatibility of organic systems. In this work, superparamagnetic poly(lactic-co-glycolic acid) (PLGA) microcapsules (Fe(3)O(4)/PLGA) have been developed, as a proof-of-concept, for the application in ultrasound/magnetic resonance dual-modality biological imaging and enhancing the therapeutic efficiency of high intensity focused ultrasound (HIFU) breast cancer surgery in vitro and in vivo. Hydrophobic Fe(3)O(4) nanoparticles were successfully integrated into PLGA microcapsules by a typical double emulsion evaporation process. In this process, highly dispersed superparamagnetic Fe(3)O(4)/PLGA composite microcapsules with well-defined spherical morphology were obtained with an average diameter of 885.6 nm. The potential of these microcapsules as dual contrast agents for ultrasonography and magnetic resonance imaging were demonstrated in vitro and, also, preliminarily in vivo. Meanwhile, the prepared superparamagnetic composite microcapsules were administrated into rabbits bearing breast cancer model for the evaluation of the in vivo HIFU synergistic ablation efficiency caused by the introduction of such microcapsules. Our results showed that the employment of the composite microcapsules could efficiently enhance ultrasound imaging of cancer, and greatly enhance the HIFU ablation of breast cancer in rabbits. In addition, pathological examination was systematically performed to detect the structural changes of the target tissue caused by HIFU ablation. This finding demonstrated that successful introduction of these superparamagnetic microcapsules into HIFU cancer surgery provided an alternative strategy for the highly efficient imaging-guided non-invasive HIFU synergistic therapy of cancer.