Tumor Therapy System Research Articles

Fibrin degradation by rtPA enhances the delivery of nanotherapeutics to A549 tumors in nude mice

Effective drug delivery to a tumor depends on favorable blood perfusion within the tumor. As an important component of tumor extracellular matrix, fibrin is abundant near tumor vessels. Inspired by the distinct distribution pattern and vessel-dependent production of fibrin, we hypothesized that fibrin depletion in tumors decompresses tumor vessels to improve tumor blood perfusion and accordingly enhance drug delivery to tumors rich in vessels. In the present study, we attempted to employ a clinically used thrombolytic drug, recombinant tissue plasminogen activator (rtPA), to modulate fibrin deposition in tumors. We then combined this drug with a nanoparticle drug delivery system for tumor therapy. RtPA treatment (25 mg/kg/d i. p. administration for two weeks) successfully depleted fibrin deposition and enhanced blood perfusion within A549 tumor xenografts. Furthermore, rtPA treatment also improved the in vivo delivery of 115-nm nanoparticles to tumor tissues. Finally, rtPA combined with therapeutic agent-loaded nanoparticles resulted in the most effective shrinkage of A549 tumor xenografts compared with the control groups. Overall, the present study provides a new strategy to enhance the delivery of nanotherapeutics to tumors rich in vessels.

Mechanism study of PEGylated polyester and β-cyclodextrin integrated micelles on drug resistance reversal in MRP1-overexpressed HL60/ADR cells

Chemotherapy is one of the main strategies for cancer treatment, but its effective application is seriously limited by the development of drug resistance. In this study, we designed micellar vectors for doxorubicin based on amphiphilic copolymers sequentially linking β-cyclodextrin (β-CD), polylacticacid (PLA) or polycaprolactone (PCL) block, and polyethylene glycol (PEG) block to overcome drug resistance in human acute myeloid leukemia cells (HL60/ADR) overexpressing multidrug resistance protein 1 (MRP1). The significant enhancement in cytotoxicity and inhibited HL60/ADR tumor growth in mouse was achieved. More importantly, several analyses were performed to understand the interactions between various polymers and MRP1 at the cellular level. The results showed that the polymers did not show remarkable correlation of MRP1 gene and protein expression, but could decrease intracellular ATP, mitochondrial membrane potential and glutathione levels, which was greatly dependent on the molecular structure of polymers. In conclusion, these novel micelles can be considered as a kind of promising drug delivery system for tumor therapy to reverse drug resistance related to MRP1 overexpression.

Comparison of the treatment effect of plasma exchange and no plasma exchange on hyperlipidemia pancreatitis

Chemotherapy is one of the main strategies for cancer treatment, but its effective application is seriously limited by the development of drug resistance. In this study, we designed micellar vectors for doxorubicin based on amphiphilic copolymers sequentially linking β-cyclodextrin (β-CD), polylacticacid (PLA) or polycaprolactone (PCL) block, and polyethylene glycol (PEG) block to overcome drug resistance in human acute myeloid leukemia cells (HL60/ADR) overexpressing multidrug resistance protein 1 (MRP1). The significant enhancement in cytotoxicity and inhibited HL60/ADR tumor growth in mouse was achieved. More importantly, several analyses were performed to understand the interactions between various polymers and MRP1 at the cellular level. The results showed that the polymers did not show remarkable correlation of MRP1 gene and protein expression, but could decrease intracellular ATP, mitochondrial membrane potential and glutathione levels, which was greatly dependent on the molecular structure of polymers. In conclusion, these novel micelles can be considered as a kind of promising drug delivery system for tumor therapy to reverse drug resistance related to MRP1 overexpression.

Magnetic nanoparticles for targeted therapeutic gene delivery and magnetic-inducing heating on hepatoma

Gene therapy holds great promise for treating cancers, but their clinical applications are being hampered due to uncontrolled gene delivery and expression. To develop a targeted, safe and efficient tumor therapy system, we constructed a tissue-specific suicide gene delivery system by using magnetic nanoparticles (MNPs) as carriers for the combination of gene therapy and hyperthermia on hepatoma. The suicide gene was hepatoma-targeted and hypoxia-enhanced, and the MNPs possessed the ability to elevate temperature to the effective range for tumor hyperthermia as imposed on an alternating magnetic field (AMF). The tumoricidal effects of targeted gene therapy associated with hyperthermia were evaluated in vitro and in vivo. The experiment demonstrated that hyperthermia combined with a targeted gene therapy system proffer an effective tool for tumor therapy with high selectivity and the synergistic effect of hepatoma suppression.

Versatile reticular polyethylenimine derivative-mediated targeted drug and gene codelivery for tumor therapy.

The study is aimed to develop a versatile reticular polyethylenimine (PEI) derivative eprosartan-g-PEI (ESP) conjugate-mediated targeted drug and gene codelivery system for tumor therapy. Eprosartan (ES), an angiotensin II type 1 receptor blocker (ARB), which has been proven to exert beneficial effects on tumor progression, vascularization, and metastasis as the conventional antihypertensive drug, was conjugated with PEI-1.8K chains into ESP via a bis-amide bond of pH-sensitivity to overcome high cytotoxicity and nontargeted gene delivery of PEI-25K. P53 gene was encapsulated in the ESP to form the codelivery system of ESP/p53 complexes, and this system was comprehensively characterized. In vitro ESP/p53 complexes had a significant effect on inhibiting angiogenesis by reducing the expression and secretion of VEGF. In vivo the effective antitumor activity of ESP/p53 complexes was observed on nude mice bearing PANC-1 xenografts, and the microvessel density (MVD) examination demonstrated that ESP/p53 complex-produced antitumor efficacy was closely correlated with the efficient angiogenesis repression. These findings disclosed that the multifunctional ESP/p53 complexes might be a promising dual anticancer drug and gene codelivery system.

Construction of hyaluronic acid noisome as functional transdermal nanocarrier for tumor therapy

To develop a functional nanosized transdermal drug delivery system for tumor therapy, amphiphilic hyaluronic acid (HA) based niosome was constructed combining transdermal and tumor targeting ability in one entity. HA esterified with monostearin, the conjugate labeled as HA–GMS self-assembled onto niosome surface and formed HA–niosome. The multilayer vesicle had small size (around 40nm), good stability and desirable drug encapsulating efficacy, and well compatible with blood. It exhibited better endocytosis to mouse breast tumor cell (4T1) than the control chitosan nanoparticle, which was verified qualitatively and quantitatively. Skin permeation of HA–niosome was proven to be efficient using in vitro stratum corneum model and in vivo fluorescence observation. Histological section study confirmed the security and efficiency of transdermal permeation. The results evidence HA–niosome to be exciting and promising for tumor therapy through trandermal administration.

One-pot synthesis of sustained-released doxorubicin silica nanoparticles for aptamer targeted delivery to tumor cells

Site-specific delivery of drugs can significantly reduce drug toxicity and increase the therapeutic effect. Here, we report a one-pot synthesis of doxorubicin-doped silica nanoparticles (Dox/SiNPs) by using sodium fluoride (NaF) catalyzed hydrolysis of tetraethyl orthosilicate in a water-in-oil microemulsion. Through further surface chemical modification, carboxyl-terminated Dox/SiNPs (COOH-Dox/SiNPs) exhibiting high drug entrapment efficiency, strong fluorescence and long sustained release are obtained. Cell toxicity tests demonstrate that the COOH-Dox/SiNPs kill tumor cells effectively, while pure COOH-SiNPs are nontoxic. An aptamer is further conjugated to the nanoparticles for delivering loaded Dox to target cells. It is demonstrated that Dox/SiNPs modified with the aptamer sgc8c (sgc8c-Dox/SiNPs) could deliver loaded doxorubicin to CCRF-CEM cells with high specificity and excellent efficiency. Furthermore, ex vivo imaging studies show that the COOH-Dox/SiNPs are able to accumulate highly in the tumor areas, thanks to the enhanced permeability and retention (EPR) effects. Our data suggest that the sgc8c-Dox/SiNPs may be a useful new tumor therapy system.

“Intelligent” nanoassembly for gene delivery: In vitro transfection and the possible mechanism

A new “intelligent” nanoassembly (INA), consisting of a condensed core of pDNA with protamine sulfate (PS) and a dioleoylphosphatidyl ethanolamine (DOPE)-based lipid envelope containing poly(ethylene glycol)-disulfide-DOPE (PSD), was designed and investigated. The in vitro release experiment was carried out in solution containing 10 mM of Glutathione, which reflected the redox potential of the intracellular environment. The experimental result indicated that PSD possessed a good ability of self-dePEGylation and could result in efficient release of content in the reductive environment. INAs showed higher transfection efficiency and much lower cytotoxicity compared with Lipofectamine™ 2000 on HEK 293 cells. Cellular uptake and subcellular localization, as well as the quantitation of nuclear transfer demonstrated that the superior transfection efficiency of INAs could result from both enhanced cellular uptake mediated by DOPE and efficient nuclear delivery mediated by PS. The biodistribution of INAs in nude mice bearing tumor implied that this PSD-based nanoassembly loading PS/DNA could be a promising gene delivery system for tumor therapy.

Possibility of active targeting to tumor by local hyperthermia with temperature-sensitive nanoparticles

Recently, the concept of drug delivery requires that the release of encapsulated drug be produced only at the diseased site with controllable rates. Given that thermosensitive hydrogels have been widely investigated for controlled delivery based on their phase transition, we speculate that nanoparticles with the novel polymers play a key role in tumor therapy respond to thermal activity. Therefore, we here hypothesize that enhanced delivery of therapeutics might be achieved by conjugation to thermosensitive polymers, in concert with targeted hyperthermia by precisely specifying the phase transition temperature of the thermosensitive polymer. By local hyperthermia at tumor site, a targeted drug delivery system could be obtained, exploiting both the temperature-sensitive and the site-specific behaviors. The proposition may provide a new strategy into the development of a novel drug delivery system for tumor therapy.

Characterization of the YDME FEP‐BY02 tumor therapy system

The YDME FEP‐BY02 is an extracorporeal tumor therapy device that has been in clinical use in China for several years. In the USA, this device is currently under investigation for the treatment of pancreatic cancer. Prior to being submitted for an application for an Investigation Device Exemption (IDE) with the FDA, the device will be required to undergo a thorough characterization of all systems involved in patient treatment. The purpose of this research is to characterize the FEP‐BY02 and obtain data for an IDE application to the FDA for the treatment of pancreatic cancer using the FEP‐BY02. A series of acoustical characterization, in vitro, and ex vivo tests are being conducted to validate the company’s preclinical and clinical experience in China. Comparisons between three methods (radiation force balance, fiber‐optic hydrophone, and scattering hydrophone) for measuring/determining focal intensities will be used to assess the validity of the measurement techniques and evaluate acoustic output over the functional input range of the FEP‐BY02. Transparent gels impregnated with thermally sensitive markers will be used to visualize lesion formation and evaluate lesion characteristics with respect to input parameters. Thermocouples implanted in tissue mimicking thermal gels and ex vivo tissue will be use to evaluate the thermal response with respect to input parameters. Preliminary data indicate that the therapeutic ultrasound treatment system forms consistent lesions at the desired target.

High intensity focused ultrasound in the treatment of small kidney tumours— The Oxford experience

14645 Background: High-intensity focused ultrasound (HIFU) provides a potential non-invasive alternative to conventional therapies. We have been using the extracorporeal ultrasound-guided Model-JC Tumor Therapy System (HAIFU Technology Company, China) in clinical trials to evaluate the safety and feasibility of treating small renal tumours. Methods: Patients with renal tumours less than 4cm diameter and unsuitable for surgery were treated with HIFU were enrolled into this phase II prospective trial. Treatment was delivered under general anaesthesia in a single session using the Model-JC Tumor Therapy System. Magnetic resonance imaging (MRI) 12 days after treatment provided an initial assessment of response (technical success). Patients are followed-up with further MR imaging at 6 months and one year to gauge technique effectiveness. A total of 14 patients will be included in the trial. Results: Eight patients with kidney tumours have been treated to date. All eight have had pre- and 12-day post-treatment MR imaging. One patient was not included in the analysis as treatment was suspended due bowel interposition in the treatment field during therapy. MRI changes suggestive of kidney tumour response have been seen in 4/7 (57%) cases. Complete ablation has been seen in two cases and partial ablation in two cases. One patient remains disease free 12 months after HIFU. Mild transient discomfort was reported by 4/8 patients (50%), and moderate discomfort in 3/8 (38%) but more severe pain needing opiate analgesia has not been encountered in this series. Minor skin toxicity (1mm blister at the treatment site) was seen in two patients. All patients were discharged the day after the procedure. There have been no adverse effects on renal, haematological or hepatic function. Conclusions: Extracorporeal HIFU has the ability to completely ablate small renal tumours. Our early clinical experience suggests that HIFU treatment of kidney tumours is safe and extremely well tolerated. The reasons for the variability in observed response remain obscure, and reliability of tumour ablation will need to improve before extracorporeal HIFU can be proposed for wider clinical use. [Table: see text]

The safety and feasibility of extracorporeal high-intensity focused ultrasound (HIFU) for the treatment of liver and kidney tumours in a Western population

High-intensity focused ultrasound (HIFU) provides a potential noninvasive alternative to conventional therapies. We report our preliminary experience from clinical trials designed to evaluate the safety and feasibility of a novel, extracorporeal HIFU device for the treatment of liver and kidney tumours in a Western population. The extracorporeal, ultrasound-guided Model-JC Tumor Therapy System (HAIFU™ Technology Company, China) has been used to treat 30 patients according to four trial protocols. Patients with hepatic or renal tumours underwent a single therapeutic HIFU session under general anaesthesia. Magnetic resonance imaging 12 days after treatment provided assessment of response. The patients were subdivided into those followed up with further imaging alone or those undergoing surgical resection of their tumours, which enabled both radiological and histological assessment. HIFU exposure resulted in discrete zones of ablation in 25 of 27 evaluable patients (93%). Ablation of liver tumours was achieved more consistently than for kidney tumours (100 vs 67%, assessed radiologically). The adverse event profile was favourable when compared to more invasive techniques. HIFU treatment of liver and kidney tumours in a Western population is both safe and feasible. These findings have significant implications for future noninvasive image-guided tumour ablation.

377 - Cytosine Deaminase — A suicide system for tumor therapy

377 - Cytosine Deaminase — A suicide system for tumor therapy