Tumor growth inhibition through targeting liposomally bound curcumin to tumor vasculature

Increasing number of Phase I/II clinical studies have demonstrated clinical potential of curcumin for treatment of various types of human cancers. Despite significant anti-tumor efficacies and bio-safety profiles of curcumin, poor systemic bioavailability is retarding its clinical success. Efforts are now being directed toward developing stable formulations of curcumin using various drug delivery systems. To this end, herein we report on the development of a new tumor vasculature targeting liposomal formulation of curcumin containing a lipopeptide with RGDK-head group and two stearyl tails, di-oleyolphosphatidylcholine (DOPC) and cholesterol. We show that essentially water insoluble curcumin can be solubilized in fairly high concentrations (~ 500 μg/mL) in such formulation. Findings in the Annexin V/Propidium iodide (PI) binding based flow cytometric assays showed significant apoptosis inducing properties of the present curcumin formulation in both endothelial (HUVEC) and tumor (B16F10) cells. Using syngeneic mouse tumor model, we show that growth of solid melanoma tumor can be inhibited by targeting such liposomal formulation of curcumin to tumor vasculature. Results in immunohistochemical staining of the tumor cryosections are consistent with tumor growth inhibition being mediated by apoptosis of tumor endothelial cells. Findings in both in vitro and in vivo mechanistic studies are consistent with the supposition that the presently described liposomal formulation of curcumin inhibits tumor growth by blocking VEGF-induced STAT3 phosphorylation in tumor endothelium. To the best of our knowledge, this is the first report on inhibiting tumor growth through targeting liposomal formulation of curcumin to tumor vasculatures.     

Brain natriuretic peptide-guided therapy for heart failure

The drug treatment of heart failure, once simple, has become complex. Apart from a loop diuretic and digoxin, most patients should now be receiving an angiotensin-converting enzyme inhibitor (or angiotensin II receptor blocker), a beta-blocker and spironolactone. Newer drugs, such as endothelin-receptor antagonists and combined blockers of converting-enzyme and neutral endopeptidase, might soon become available. When to introduce these drugs and what dose is optimal for any individual, are questions that currently vex clinicians. We proposed that plasma levels of the cardiac hormone brain natriuretic peptide (BNP, or better, its 1-76 amino-acid N-terminal fragment, N-BNP), would provide an objective index for guiding drug treatment in patients with established, stable cardiac failure. In a pilot study, 69 patients were randomized to drug treatment based on clinical criteria, or based on plasma levels of N-BNP. After a median follow-up of 9.6 months, those in the N-BNP group had fewer clinical end-points than those in the group managed by clinical criteria alone (19 vs 54; P= 0.02). These preliminary data encourage the concept that the increasingly complex pharmacotherapy for heart failure, both chronic (as in this trial) and acute, might best be guided by an objective measure such as plasma levels of BNP or N-BNP.     

Tissue-specific promoters for cancer gene therapy

Adenoviral cancer gene therapy approaches have resulted in promising recent results. Following only a decade of intense development, some of the crucial obstacles are now being overcome. Insufficient transduction has been the main limitation of earlier approaches. A new approach for increasing transduction of tumour cells is utilisation of replication-competent oncolytic agents, such as conditionally replicating adenoviruses (CRADs). The anti-tumour effect is caused by replication of the virus per se and, thus, replication must be restricted to tumour cells to protect normal tissues from damage. Tissue-specific promoters (TSPs) represent a powerful tool for decreasing the toxicity of cancer gene therapy to normal tissues and have previously been utilised for specific mutation compensation or delivery of prodrug-converting enzymes. However, TSPs can also be used for controlling crucial viral replication regulators and consequent restriction of replication to tumour cells. Initial clinical trials have demonstrated the safety and suggested efficacy for TSP-controlled CRADs as a novel approach for cancer gene therapy.     

Molecular biology of epidermal growth factor receptor inhibition for cancer therapy

Understanding the role of the epidermal growth factor receptor (EGFR) in cellular signalling processes underlying malignancy has enabled the development of rationally designed EGFR-targeted therapeutics. Strategies have been devised to interfere with the EGFR signalling at three different levels: at the extracellular level, competing with ligand binding; at the intracellular level, inhibiting the activation of the tyrosine kinase; or at the mRNA level, modulating the expression of the EGFR protein. Each of these strategies has proven to have an antitumour effect mediated by events such as inhibition of cell proliferation, induction of apoptosis, decrease of cellular invasion and migration; and/or inhibition of angiogenesis. Furthermore, the combination of these strategies with traditional chemotherapy or radiotherapy has generally resulted in enhanced antitumour effects. Likewise, the benefit of interfering simultaneously with different signalling pathways has been documented to improve tumour growth inhibition. These preclinical results have encouraged clinical studies that led to the FDA approval of three drugs. However, finding the perfect strategy for each individual patient appears to be a limiting factor, demanding further research to be able to generate relevant molecular expression profiles on a case-to-case basis. Taken together, a successful EGFR inhibition will require a better understanding of signalling pathways in combination with the development of rationally designed effective molecules.     

Bacterial ghosts as carrier and targeting systems

Bacterial ghosts are empty cell envelopes originating from Gram-negative bacteria. They have a natural outer surface make-up which provides them with the original targeting functions of the bacteria they are derived from and are thus able to bind to and/or are taken up by specific cells or tissues of animal, human or plant origin. The extended bacterial ghost system represents a platform technology for creating new qualities in non-living carriers which can be used for the specific targeting of drugs, DNA or other compounds to overcome toxic or non-desired obstacles. Freeze dried bacterial ghosts are stable without the requirement of a cold chain and can be effectively administered orally and aerogenically as drug carriers. The new system is an alternative to liposomes and may have an advantage due to its higher specificity for targeting specific tissues, its easy method of production and its versatility in entrapping and packaging various compounds in different compartments of the carriers.     

Oncolytic adenoviruses for treatment of brain tumours

Standard therapies are not capable of curing patients with malignant glioma; more than 90% of patients die within 2 years after diagnosis. Gene therapy appeared as a promising new approach for this disease. However, results of clinical trials with replication deficient viral vectors were disappointing. The main reasons being poor transduction efficiency of adenovirus towards glioma cells and limited spread and distribution of the vector in the tumour. With the increasing knowledge of viral genetics and its functions, an attractive alternative tool to kill malignant glioma cells has been developed: Replicating adenovirus as an oncolytic agent. This type of therapy, also referred to as virotherapy, has the potential to overcome some of the limitations connected with replication deficient adenoviral vectors. In this review the authors describe the latest developments in strategies that are being used to create a tumour- or glioma- selective replicating adenovirus. Special attention is given to the methods of viral delivery to an infiltrating tumour in the brain, regarding optimal dose and toxicity. Furthermore, the role of conventional antitumour treatments, such as irradiation and chemotherapy, in enhancing the effect of virotherapy is being emphasised.     

Enhancing and targeting nucleic acid delivery by magnetic force

Insufficient contact of inherently highly active nucleic acid delivery systems with target cells is a primary reason for their often observed limited efficacy. Physical methods of targeting can overcome this limitation and reduce the risk of undesired side effects due to non-target site delivery. The authors and others have developed a novel means of physical targeting, exploiting magnetic force acting on nucleic acid vectors associated with magnetic particles in order to mediate the rapid contact of vectors with target cells. Here, the principles of magnetic drug and nucleic acid delivery are reviewed, and the facts and potentials of the technique for research and therapeutic applications are discussed. Magnetically enhanced nucleic acid delivery – magnetofection – is universally applicable to viral and non-viral vectors, is extraordinarily rapid, simple and yields saturation level transfection at low dose in vitro. The method is useful for site-specific vector targeting in vivo. Exploiting the full potential of the technique requires an interdisciplinary research effort in magnetic field physics, magnetic particle chemistry, pharmaceutical formulation and medical application.     

The role of cathelicidin and defensins in pulmonary inflammatory diseases

Antimicrobial peptides (AMPs) protect the epithelia of mucosal organs like the respiratory or the gastrointestinal tract from invading microorganisms. As an integral part of the innate immune system they display antimicrobial activity against Gram- and Gram-negative bacteria as well as against fungi and enveloped and non-enveloped viruses. Besides their microbicidal effects they have important functions in the regulation of repair and inflammation. AMPs are sometimes referred to as ‘alarmins’ due to their ability to recruit, modulate and activate components of the immune system. In contrast, some AMPs suppress activation of the immune system. AMPs are also involved in tissue repair, cancer biology and angiogenesis. Based on their antimicrobial and immunomodulatoy functions, AMPs are probably involved in the pathogenesis of infectious and inflammatory diseases of the lung. Inborn or acquired deficiencies contribute to susceptibility to infection and colonisation. The potential pro-inflammatory role of AMPs contributes to the disease processes in inflammatory disorders such as asthma, chronic obstructive pulmonary disease, sepsis or pulmonary fibrosis. This review summarises the knowledge about the functions of AMPs in the pulmonary innate host defence system and their role in respiratory disease.     

Antifungal drug resistance mechanisms

The present view focuses on the possibility that cationic antimicrobial peptides (CAMPs) might, in addition to their killing effects due to permeabilization of microbial membranes, also function similarly to β-lactam antibiotics to activate nascent autolytic wall enzymes, leading to bacteriolysis. Since the massive release of microbial cell wall components is a major cause of postinfectious sequelae, the in vivo process of bacteriolysis must be controlled. Due to the emergence of antibiotic resistance in pathogenic bacteria, CAMPs might be useful as an alternative to antibiotics. However, they should be used with caution, since they might also function as a ‘double-edged sword’ by injuring both the bacteria and host.