Novel percutaneous adventitial drug delivery system for regional vascular treatment.

A novel intracoronary microsyringe system (MicroSyringe) was developed for regulated drug injection into the adventitial space. In this report, the feasibility, safety, and distribution pattern of vascular treatment with this modality were tested in 17 swine by delivering Oregon green-labeled paclitaxel (OGP) and tacrolimus. Coronaries were harvested 0.5-96 hr postinjection and analyzed for drug by fluorescence histochemistry (OGP) and liquid chromatography-mass spectrometry (tacrolimus). Histopathological analysis was subsequently performed. The microsyringe deliveries were performed safely in all cases. In the OGP-injected group, within 2 hr postprocedure there was intense staining of the adventitia, media, and endothelium around the injection site, and by 23 hr staining extended distally by 27.5 mm. With tacrolimus, similar longitudinal drug distribution was seen; furthermore, by 48 hr there was detectable drug over 40 mm proximal and distal to the injection site. Significant levels of tacrolimus were detectable in coronaries at 96 hr. Percutaneous adventitial delivery is safe, feasible, and provides consistent dosing for complete treatment of a vascular territory.     

Angiogenic therapy for cardiac repair based on protein delivery systems

Cardiovascular diseases remain the first cause of morbidity and mortality in the developed countries and are a major problem not only in the western nations but also in developing countries. Current standard approaches for treating patients with ischemic heart disease include angioplasty or bypass surgery. However, a large number of patients cannot be treated using these procedures. Novel curative approaches under investigation include gene, cell, and protein therapy. This review focuses on potential growth factors for cardiac repair. The role of these growth factors in the angiogenic process and the therapeutic implications are reviewed. Issues including aspects of growth factor delivery are presented in relation to protein stability, dosage, routes, and safety matters. Finally, different approaches for controlled growth factor delivery are discussed as novel protein delivery platforms for cardiac regeneration.     

Micromanaging cardiac regeneration:Targeted delivery of micro RNAs for cardiac repair and regeneration

The loss of cardiomyocytes during injury and disease can result in heart failure and sudden death, while the adult heart has a limited capacity for endogenous regeneration and repair. Current stem cell-based regenerative medicine approaches modestly improve cardiomyocyte survival, but offer neglectable cardiomyogenesis. This has prompted the need for methodological developments that crease de novo cardiomyocytes. Current insights in cardiac development on the processes and regulatory mechanisms in embryonic cardiomyocyte differentiation provide a basis to therapeutically induce these pathways to generate new cardiomyocytes. Here, we discuss the current knowledge on embryonic cardiomyocyte differentiation and the implementation of this knowledge in state-ofthe-art protocols to the direct reprogramming of cardiac fibroblasts into de novo cardiomyocytes in vitro and in vivo with an emphasis on micro RNA-mediated reprogramming. Additionally, we discuss current advances on state-of-theart targeted drug delivery systems that can be employed to deliver these micro RNAs to the damaged cardiac tissue. Together, the advances in our understanding of cardiac development, recent advances in micro RNAbased therapeutics, and innovative drug delivery systems, highlight exciting opportunities for effective therapies for myocardial infarction and heart failure.     

Iontophoresis for modulation of cardiac drug delivery in dogs.

Cardiac arrhythmias are a frequent cause of death and morbidity. Conventional antiarrhythmia therapy involving oral or intravenous medication is often ineffective and complicated by drug-associated side effects. Previous studies from our laboratory have demonstrated the advantages of cardiac drug-polymer implants for enhanced efficacy for cardiac arrhythmia therapy compared with conventional administration. However, these studies were based on systems that deliver drugs at a fixed release rate. Modulation of the drug delivery rate has the advantage of regulating the amount of the drug delivered depending upon the disease state of the patient. We hypothesized that iontophoresis could be used to modulate cardiac drug delivery. In this study, we report our investigations of a cardiac drug implant in dogs that is capable of iontophoretic modulation of the administration of the antiarrhythmic agent sotalol. We used a heterogeneous cation-exchange membrane (HCM) as an electrically sensitive and highly efficient rate-limiting barrier on the cardiac-contacting surface of the implant. Thus, electric current is passed only through the HCM and not the myocardium. The iontophoretic cardiac implant demonstrated in vitro drug release rates that were responsive to current modulation. In vivo results in dogs have confirmed that iontophoresis resulted in regional coronary enhancement of sotalol levels with current-responsive increases in drug concentrations. We also observed acute current-dependent changes in ventricular effective refractory periods reflecting sotalol-induced refractoriness due to regional drug administration. In 30-day dog experiments, iontophoretic cardiac implants demonstrated robust sustained function and reproducible modulation of drug delivery kinetics.     

Use of an implantable drug delivery system for refractory chronic sickle cell pain

An increasing number of chronic sickle cell patients are being treated with sustained-release opioids in the same manner as cancer patients. In a randomized clinical trial of patients with refractory cancer pain, implantable intrathecal drug delivery systems (IDDS) improved clinical success compared to comprehensive medical management alone. We implanted IDDS pumps in two sickle cell patients with refractory bone pain. Both patients achieved rapid and sustained relief of pain, with dramatic reduction in the use of as-needed opioids, crises, and admissions. IDDS may offer relief for sickle cell patients with refractory pain. A prospective trial with more participants is planned.     

心原性恶病质的药物治疗进展

心原性恶病质是不同病因导致的慢性心力衰竭晚期的一种严重并发症,伴随患者进行性体质量下降,骨骼肌和脂肪组织减少。心原性恶病质的发病机制复杂,主要机制有神经激素激活、免疫和炎性反应激活、代谢失衡及胃肠功能改变等。目前尚无关于心原性恶病质预防及治疗的临床指南,根据其病理生理机制进行相应的药物治疗为临床提供了可行的方案。该文介绍心原性恶病质的药物治疗进展。     

Stem cells for cardiac repair: an introduction

Cardiovascular disease is a major cause of morbidity and mortality throughout the world. Most cardiovascular diseases, such as ischemic heart disease and cardiomyopathy, are associated with loss of functional cardiomyocytes. Unfortunately, the heart has a limited regenerative capacity and is not able to replace these cardiomyocytes once lost. In recent years, stem cells have been put forward as a poten-tial source for cardiac regeneration. Pre-clinical studies that use stem cell-derived cardiac cells show promising results. The mechanisms, though, are not well understood, results have been variable, sometimes transient in the long term, and often without a mechanistic explana-tion. There are still several major hurdles to be taken. Stem cell-derived cardiac cells should resemble original cardiac cell types and be able to integrate in the damaged heart. Integration requires administration of stem cell-derived cardiac cells at the right time using the right mode of delivery. Once delivered, transplanted cells need vascularization, electrophysiological coupling with the injured heart, and prevention of immunological rejection. Finally, stem cell therapy needs to be safe, reproducible, and affordable. In this review, we will give an introduction to the principles of stem cell based cardiac repair.     

Tumor-specific targeting of an anticancer drug delivery system by LHRH peptide

The central problem in cancer chemotherapy is the severe toxic side effects of anticancer drugs on healthy tissues. Invariably the side effects impose dose reduction, treatment delay, or discontinuance of therapy. To limit the adverse side effects of cancer chemotherapy on healthy organs, we proposed a drug delivery system (DDS) with specific targeting ligands for cancer cells. The proposed DDS minimizes the uptake of the drug by normal cells and enhances the influx and retention of the drug in cancer cells. This delivery system includes three main components: (i) an apoptosis-inducing agent (anticancer drug), (ii) a targeting moiety-penetration enhancer, and (iii) a carrier. We describe one of the variants of such a system, which utilizes camptothecin as an apoptosis-inducing agent and poly(ethylene glycol) as a carrier. Luteinizing hormone-releasing hormone (LHRH) was used as a targeting moiety (ligand) to LHRH receptors that are overexpressed in the plasma membrane of several types of cancer cells and are not expressed detectably in normal visceral organs. The results showed that the use of LHRH peptide as a targeting moiety in the anticancer DDS substantially enhanced the efficacy of chemotherapy, led to amplified apoptosis induction in the tumor, and minimized the side effects of the anticancer drug on healthy organs. The LHRH receptor targeting DDS did not show in vivo pituitary toxicity and did not significantly influence the time course or the plasma concentration of luteinizing hormone and its physiological effects on the reproductive functions of mice.     

Totally implanted drug delivery system for hepatic arterial chemotherapy

A totally implanted drug delivery system for hepatic arterial chemotherapy was evaluated in 13 patients with metastatic (11 colon and one carcinoid) or primary (one hepatoma) cancer of the liver. During laparotomy, a Silastic catheter was positioned in the hepatic artery for infusion to the entire liver arterial vasculature as ascertained by low-flow radionuclide angiography with 99Tc-macroaggregated albumin. The catheter was connected to a subcutaneously implanted model 400 Infusaid pump (Metal Bellows Corp, Sharon, MA). Each pump had a 50-ml volume and a set rate (3--6 ml/day) and required refill every 8--16 days. A side port bypassed the pumping mechanism and allowed direct catheter injection for nuclide angiography, for bolus drug administration, or for clearing of a blocked catheter. Pump refills and side port injections were performed by percutaneous injection. The 13 patients in this ongoing study received a median of 6 months (range, 4.5--17) of continuous hepatic arterial infusion. The pump performed reliably with stable (+/- 10%) flow rates and only one malfunction in 2800 cumulative days of use. Flow distribution determined by low-flow radionuclide angiography did not change in 12 patients. Patient acceptance was excellent, with the ability to participate fully in normal daily activities. Eleven patients showed partial hepatic tumor regressions documented by physical examination and nuclide liver scans. All patients were treated with 5-fluorodeoxyuridine. Two patients failed 5-fluorodeoxyuridine therapy and subsequently responded briefly to dichloromethotrexate. This implanted system should facilitate future investigation of regional chemotherapy using these and other agents.     

Stable therapeutic effects of mesenchymal stem cell-based multiple gene delivery for cardiac repair

AIMS: We have previously shown that transplantation of mesenchymal stem cells (MSCs) co-overexpressing angiopoietin-1 (Ang-1) and Akt prevented cell apoptosis, enhanced angiogenesis, and improved left ventricular heart function. The present study was designed to determine the persistence of therapeutic benefits on longer term basis. METHODS AND RESULTS: Acute myocardial infarction model was developed in 30 young female Fischer-344 rats by permanent ligation of the left anterior descending coronary artery. The animals were grouped (n = 10) to receive 70 microL Dulbecco's modified Eagle's medium (DMEM) without cells (DMEM group 1) or containing 3 x 10(6) non-transduced male MSCs (MSC group 2) or transduced MSCs co-overexpressing Ang-1 and Akt (MAA group 3). The injections were carried out intramyocardially in the free wall of left ventricle at multiple sites. Three months after cell transplantation, real-time polymerase chain reaction for the rat sry gene, confocal imaging, and immunohistochemical studies revealed the extensive survival and myogenic differentiation of the PKH67-labelled cell graft. Blood vessel density was significantly higher in the MAA group (P < 0.05) at 3 months compared with the other groups. Blood vessel maturation index as determined by double-fluorescent immunostaining for vWFactor VIII and smooth muscle actin showed that most of the newly formed vessels matured to develop a smooth muscle covering in MAA group. Sonographic assessment of heart function showed that heart function deteriorated in the DMEM group, whereas the functional benefits were stable over a period of 3 months following transplantation of transfected cells. CONCLUSION: Engraftment of genetically modified MSCs co-overexpressing Ang-1 and Akt produced long-term histological and functional benefits in an infarcted heart.     

Hydrogel drug delivery system with predictable and tunable drug release and degradation rates

Many drugs and drug candidates are suboptimal because of short duration of action. For example, peptides and proteins often have serum half-lives of only minutes to hours. One solution to this problem involves conjugation to circulating carriers, such as PEG, that retard kidney filtration and hence increase plasma half-life of the attached drug. We recently reported an approach to half-life extension that uses sets of self-cleaving linkers to attach drugs to macromolecular carriers. The linkers undergo β-eliminative cleavage to release the native drug with predictable half-lives ranging from a few hours to over 1 y; however, half-life extension becomes limited by the renal elimination rate of the circulating carrier. An approach to overcoming this constraint is to use noncirculating, biodegradable s.c. implants as drug carriers that are stable throughout the duration of drug release. Here, we use β-eliminative linkers to both tether drugs to and cross-link PEG hydrogels, and demonstrate tunable drug release and hydrogel erosion rates over a very wide range. By using one β-eliminative linker to tether a drug to the hydrogel, and another β-eliminative linker with a longer half-life to control polymer degradation, the system can be coordinated to release the drug before the gel undergoes complete erosion. The practical utility is illustrated by a PEG hydrogel–exenatide conjugate that should allow once-a-month administration, and results indicate that the technology may serve as a generic platform for tunable ultralong half-life extension of potent therapeutics.     

Local drug delivery: an emerging approach in the treatment of restenosis

Very limited success has been demonstrated with systemic pharmacological treatment to reduce the incidence of restenosis following angioplasty in patients. The lack of success of many of the pharmacotherapeutic agents in reducing the restenosis rates post-angioplasty and following stent implementation is believed to arise from inadequate concentrations of the agents at the lesion site. This has led to the development of various local delivery devices that would ideally deliver and retain adequate amounts of drug to the vessel wall for sufficient periods of time to ensure a therapeutic effect without inducing further injury or compromising blood flow. Local dosing would avoid systemic toxicity, and the use of modified balloon catheters or coated stents might enable percutaneous approaches.     

Implantation of a drug delivery system during surgery for patients with primary hepatocarcinoma

BACKGROUND: Postoperative regional chemotherapy is one of the most effective methods to decrease the recurrent rate and improve the prognosis of primary hepatocarcinoma (PHC). This study was undertaken to assess the optimal pathway to implant the drug delivery system (DDS) in the different ways of resecting PHC so as to offer a valuable reference to clinical implantation of the DDS. METHODS: One hundred and ninety cases were divided into two groups according to whether the tumors were resected completely (A) or not (B). Groups A and B were subdivided into three groups a, b and c according to the pathway selected for DDS implantation. The patients in subgroup a received DDS implantation through both the hepatic artery and portal vein (A+P-implanted group), the patients in subgroup b received DDS implantation through the portal vein (P-implanted group), and the patients in subgroup c received DDS implantation through the hepatic artery (A-implanted group). RESULTS: The 1- and 3-year recurrent rates of subgroup c in group A were higher than those of subgroup b, and there was no significant difference between subgroups a and b. Compared with subgroups a and c, the 1- and 3-year survival rates of subgroup b were similar to those of group a but higher than those of group c. The 1- and 3-year survival rates between subgroups a and b in group B were significantly different. The prognosis of subgroup c was lower than that of subgroup a and no significant difference was observed between subgroups b and c. CONCLUSIONS: The DDS should be implanted into the portal vein when PHC is resected completely. It may be better to implant it into both portal vein and hepatic artery if the tumor cannot be completely resected.     

Gastroretentive drug delivery systems for the treatment of Helicobacter pylori

Helicobacter pylori (H. pylori) is one of the most common pathogenic bacterial infections and is found in the stomachs of approximately half of the world’s population. It is the primary known cause of gastritis, gastroduodenal ulcer disease and gastric cancer. However, combined drug therapy as the general treatment in the clinic, the rise of antibiotic-resistant bacteria, adverse reactions and poor patient compliance are major obstacles to the eradication of H. pylori. Oral site-specific drug delivery systems that could increase the longevity of the treatment agent at the target site might improve the therapeutic effect and avoid side effects. Gastroretentive drug delivery systems potentially prolong the gastric retention time and controlled/sustained release of a drug, thereby increasing the concentration of the drug at the application site, potentially improving its bioavailability and reducing the necessary dosage. Recommended gastroretentive drug delivery systems for enhancing local drug delivery include floating systems, bioadhesive systems and expandable systems. In this review, we summarize the important physiological parameters of the gastrointestinal tract that affect the gastric residence time. We then focus on various aspects useful in the development of gastroretentive drug delivery systems, including current trends and the progress of novel forms, especially with respect to their application for the treatment of H. pylori infections.     

Micelles as potential drug delivery systems for colorectal cancer treatment

Despite the significant progress in cancer therapy, colorectal cancer (CRC) remains one of the most fatal malignancies worldwide. Chemotherapy is currently the mainstay therapeutic modality adopted for CRC treatment. However, the long-term effectiveness of chemotherapeutic drugs has been hampered by their low bioavailability, non-selective tumor targeting mechanisms, non-specific biodistribution associated with low drug concentrations at the tumor site and undesirable side effects. Over the last decade, there has been increasing interest in using nanotechnology-based drug delivery systems to circumvent these limitations. Various nanoparticles have been developed for delivering chemotherapeutic drugs among which polymeric micelles are attractive candidates. Polymeric micelles are biocompatible nanocarriers that can bypass the biological barriers and preferentially accumulate in tumors via the enhanced permeability and retention effect. They can be easily engineered with stimuli-responsive and tumor targeting moieties to further ensure their selective uptake by cancer cells and controlled drug release at the desirable tumor site. They have been shown to effectively improve the pharmacokinetic properties of chemotherapeutic drugs and enhance their safety profile and anticancer efficacy in different types of cancer. Given that combination therapy is the new strategy implemented in cancer therapy, polymeric micelles are suitable for multidrug delivery and allow drugs to act concurrently at the action site to achieve synergistic therapeutic outcomes. They also allow the delivery of anticancer genetic material along with chemotherapy drugs offering a novel approach for CRC therapy. Here, we highlight the properties of polymeric micelles that make them promising drug delivery systems for CRC treatment. We also review their application in CRC chemotherapy and gene therapy as well as in combination cancer chemotherapy.     

Combining pharmacological mobilization with intramyocardial delivery of bone marrow cells over-expressing VEGF is more effective for cardiac repair

We postulated that combining cell based hVEGF165 gene delivery with cytokine-induced mobilization of bone marrow cells (BMC) may give better prognosis in an infarcted heart. Forty-eight myoabalated female C57BL/6J mice (20-25 g) received 1 x 10(6) BMC from transgenic GFP+ male mice. One month later, acute myocardial infarction (MI) model was developed by coronary artery ligation. Animals were grouped (N = 12) to receive intramyocardial injections of 10 microl DMEM without cells (group 1; group 2) or with 1x10(5) mesenchymal stem cells (MSC) over-expressing hVEGF165 (group 3; group 4). The animals received either cytokine therapy (group 2 and 4) or saline solution (group 1 and 3) for 7 days after MI. Hemodynamic data were obtained 4 weeks after MI using Millar's P-V system and cardiac tissue was harvested for immunohistological studies. We observed regeneration and extensive survival of BMC in and around the infarcted myocardium in groups 3 and 4. Blood vessel density was markedly enhanced in group 4 as compared with groups 1 and 2 in peri-infarct area. Fibrotic area was significantly reduced with improved LV-contractile function in group 2 and 4. LV-systolic and diastolic functions were well-preserved in group 4 as indicated by +dP/dt, -dP/dt and Tau (glantz). We therefore conclude that transplantation of MSC overexpressing VEGF combined with cytokine induced BMC mobilization is superior to either of the monotherapy approach for angiomyogenesis and LV-function recovery.