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Experiment Study on Polylactic Acid Microbubble Ultrasonic Contrast Agents for Drug Delivery

Author: PanJie
Tutor: ZhangQiQing；HouZhenQing
School: Xiamen University
Course: Biomedical Engineering
Keywords: Microbubble ultrasound contrast agents Polylactic acid SPG membrane emulsification technique Hydroxycamptothecin Drug operation and release system
CLC: R73-36
Type: Master's thesis
Year: 2009
Downloads: 175
Quote: 1
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Abstract

Cancer is one of the major diseases that threaten human health, and the treatment of malignant tumors in a large extent still chemotherapy. Hydroxycamptothecin (HCPT) is a broad-spectrum anticancer drugs, clinical available as a lyophilized powder for injection. Biocompatible and biodegradable polylactic acid (PLA), has a wide range of applications in the biomedical field. In order to increase the plasma concentration of the target sites, reduce the dose to reduce the toxic side effects, carrier hydroxycamptothecin PLA microbubble ultrasound contrast agent microbubbles targeted drug operation and release system for future research and development of drug-loaded PLA ultrasound contrast agent targeted drug operation and release system to provide an experimental basis. Ultrasonic positioning targeting drug-loaded microbubble ultrasound contrast agent is a use of ultrasound to locate and release targeted drug operation and release system. Biodegradable polymer polymer PLA material using the phacoemulsification combined SPG membrane emulsification and freeze-drying technology preparation of drug-loaded microbubble ultrasound contrast agent containing perfluoropropane (C _{3 F ₈) gas. Can be determined by ultrasound imaging microbubble ultrasound cavitation effect can microbubble rupture, releasing the drug, so as to achieve an increase in blood concentration of target sites, reduce the dosage, the location in the body, reducing the toxic side effects and targeted drug delivery purposes. Ultrasound positioning targeting drug-loaded microbubble ultrasound contrast agents opened up a whole new field of study, ultrasonic diagnostic equipment can be visually observed microbubbles run to the target site, the use of passive targeting mechanisms and ultrasonic cavitation effect microbubbles rupture, drug release at the target site, to achieve the purpose of targeting administration. The ultrasonic positioning targeting drug-loaded microbubble ultrasound contrast agents can be used to thrombosis diagnosis and treatment, the tumor vascular embolization and chemotherapy, gene therapy and other fields, has a broad application prospects and major clinical significance. Polylactic acid capsule wall material the hydroxycamptothecin wrapped drugs the carrier hydroxycamptothecin the PLA microbubble ultrasound contrast agent preparation. The specific contents are summarized as follows: 1 through phacoemulsification method and ultrasonic emulsification combined SPG micro-membrane emulsification method for preparation of findings of non-drug-loaded PLA microbubbles found that both methods can be prepared microbubble ultrasound contrast agents suitable particle size particle size uniformity of ultrasonic emulsification combined the SPG micro membrane emulsification microbubbles prepared better than the phacoemulsification prepared microbubbles. (1) Preparation of phacoemulsification method ideal process and parameters as follows: under the action of ultrasonic wave (80W · 10S · 10 times), 1ml inner water phase with uniform injection dissolved 0.025g/ml PDLLA and 1.0% Span80 10ml oil phase to form W ₁ / O primary emulsion, then W ₁ / O early emulsion uniform injection of ultrasonic (200W · 10S · 6) under the action of 100ml contains 1.0% Tween 80 emulsifier, external aqueous phase to form a W ₁ / O / W ₂ complex emulsion, the multiplexed water emulsion was poured into 1000ml of 1.0% PVA as stabilizer phase, a constant temperature of 40 ° C and continuing 100rpm/min low speed magnetic stirring overnight, the 3000g was centrifuged 10min, microbubbles were collected precipitate. In this method can prepare the particle size of the microbubbles located at the three peaks, wherein 19.5% of the average particle diameter of microbubbles 238.1nm, 34.3% of the microbubbles an average particle diameter of 1.713μm, another 46.2% of the microbubbles of an average particle diameter 3.961μm. (2) ultrasonic emulsification combined the SPG micro membrane emulsification method ideal preparation processes and parameters: ultrasonic (80W · 10S · 10 times) under the action of 1ml of water uniform injection of dissolved 0.025g/ml PDLLA and 1.0% Span80, 10ml outside the oil phase to form W ₁ / O primary emulsion after the beginning of the emulsion into the the SPG micro membrane emulsification pressure tanks, select the 1.1μm aperture SPG membrane and regulation of high purity nitrogen pressure 50kpa over SPG micromembrane into this colostrum hydraulic 1.0% PVA dispersion stability of W ₁ / O / W ₂ complex milk, 40 ℃ the thermostatic continued 100rpm/min The low-speed magnetic stirring overnight, the 3000g was centrifuged 10min, microbubbles were collected precipitate. The Preparation of microbubbles, and the remaining 93.6% of the microbubbles in addition to 6.4% of the average particle diameter of 274nm outer average particle diameter of 4.124μm, uniformity is obviously better than the Preparation of the phacoemulsification microbubbles. On the basis of the non-drug-loaded PLA microbubbles Preparation of combined ultrasound emulsification SPG micro-membrane emulsification method contained hydroxycamptothecin PLA microbubbles preparation methods, with different concentrations of hydroxy camptothecin sodium hydroxide the result of the influence of the weak alkali solution as the inner water phase, pH6.0 containing 1.0% PVA aqueous solution of dilute hydrochloric acid for the external aqueous phase, the study within the aqueous phase of drug concentration on the rate of drug loading and encapsulation efficiency of the microbubbles that, when the inner water phase drug concentration 4mg/ml, the encapsulation efficiency of the microbubbles prepared highest value of 66.48%, and when the inner aqueous phase drug concentration 4mg/ml microbubbles prepared drug loading rate reaches a maximum value of 1.084%. Scanning electron microscopy revealed that the average particle diameter of about 5μm prepared drug loading of microbubbles, smooth surface and rounded. 3 experiments in vitro release of the drug-loaded microbubbles found in the 37 ° C, 100 rpm / min under the conditions of Thermostat oscillation week microbubbles accumulated release percentage was 64.14%, in vitro 3.5MHz MI1.0 under conditions, ultrasonic 90s / cumulative percentage of 94.37% times 3 times ultrasound after release the microbubbles drug released almost entirely. Drug-loaded microbubbles found in New Zealand white rabbits in vivo drug release experiment, better than ordinary liquid injection drugs, plasma concentration of microbubbles download drugs in the same conditions, be able to maintain a relatively constant plasma concentration over an extended period drug delivery effect. Drug-loaded microbubbles anti the Kunming mouse H ₂₂ tumor animal experiments show that the drug-loaded microbubbles combined tumor targeting ultrasound, anti-tumor effect than the blank group under the conditions of the same dose, simply use the hydroxyl the camptothecin group, and the drug-loaded microbubbles ultrasound group significantly. 6 drug-loaded microbubble ultrasound contrast agents in New Zealand white rabbits cardiac ultrasound imaging studies show that the injection of microbubbles has been fully filling 20mg right ventricular and left ventricular opacification prepared drug-loaded microbubble ultrasound contrast agent smoothly through the pulmonary circulation, the appropriate particle size, while the echo effect, good contrast, and in line with the purpose of this paper and requirements.}

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