Current Cancer Drug Targets - Volume 3, Issue 4, 2003

Aerosol delivery of drugs holds promise for a number of diseases. The large blood vessel network feeding the lungs make them accessible from the intravenous route, and the endothelium and lung parenchyma have been targeted intravenously for a number of drugs. However, the easy access of the lungs through the pulmonary airways has not been extensively utilized except for a few disease areas and drugs. The last few years have witnessed a rejuvenation of aerosol drug delivery, with a number of pharmaceutical firms taking the lead in developing aerosolized insulin for diabetes. Pfizer, Aventis and Inhale Therapeutics recently presented the results of a clinical study with patients receiving aerosolized insulin. The pharmacokinetics of aerosolized insulin, as well as its ability to maintain blood sugar levels, was much better in comparison to intramuscular insulin. Eli Lilly is also developing a similar formulation of insulin. The benefits are obvious - painless delivery of drug with a similar or better pharmacokinetics. However, certain concerns regarding the side effects remain to be addressed. Still, these advances have boosted the aerosol drug delivery field. This hot topic issue focuses on aerosol delivery of therapeutics for pulmonary diseases, specifically lung cancer. In the first review Rao et al., discuss the delivery of cytokines for malignancy of the lung. They primarily focus on three cytokines: interleukin-2 (IL-2), interferon gamma (INF-γ) and granulocyte macrophage cytokine stimulating factor (GM-CSF). The contrast between the aerosol delivery vs. other modes of delivery such as intravenous, intraperitoneal and intramuscular is presented through a review of both animal and human studies. Pharmacokinetic evaluations of the intravenously administered IL-2 demonstrate that it is rapidly eliminated with an initial and terminal elimination half-life of 6-12 minutes and 40-80 minutes, respectively. Inhaled IL-2, in contrast, has been shown to lead to a dose dependent increase in the numbers of memory T lymphocytes, macrophages, and eosinophils in BAL fluid. Effective activation of lymphocytes is achieved, with an increase in the expression of adhesion molecules on lymphocytes in the BAL fluid, and in the capacity to produce cytokines. A liposomal and free formulation of IL-2 rendered mice tumor free after IL-2 therapyvz; and the aerosol route was more effective than the intraperitoneal and subcutaneous routes in C57BL / 6 mice with MCA-106 sarcoma pulmonary metastases. Mice treated with the aerosolized drug also had significantly fewer numbers of gross pulmonary metastases and better survival than controls. Minimal toxicity was observed. Further, the liposomal formulation had better therapeutic efficacy when compared to the free IL-2 formulation. In human studies, toxicity from the inhaled therapy was minimal with the therapy not being stopped in any patient. In comparison, subcutaneous IL-2 therapy had to be stopped in 2 patients, and IFN-α had to be discontinued in 6 patients because of local and systemic side effects such as fever, malaise and arthralgias. Further, using standard response criteria, 1 complete remission, 8 partial remissions, and 6 patients with stable disease in lung metastases were reported. In 7 patients who had extrapulmonary metastases, 3 had partial remissions and one had stable disease. The mean survival in this group was 19.1 months, as compared to an expected survival of 9.9 months. Apart from these objective responses, a significant proportion of patients had stabilization of disease for prolonged periods of time (up to 6 months in 40% of patients), including one patient who had been clearly progressing up to the time of enrollment. Similar studies and results are reviewed and discussed for IFN-γ and GM-CSF. In the next review, Koshkina and colleagues, discuss an exciting drug, camptothecin (CPT), which is a topoisomerase I inhibitor. After reviewing the chemistry and pharmacology of the drug, the authors explore the various derivatives of the drug, liposomal formulations used for aerosol delivery and various disease models showing the promising effect of the drug. Recently published studies of solid lipid nanoparticles (SLN) used as delivery vehicles for CPT are reviewed. SLN are colloidal drug carriers that combine the advantages of polymeric nano / microspheres, fat emulsions and liposomes and may be used for intravenous administration. Change in pharmacokinetics by employing microsphere and nanoparticle formulation, may reduce maximum concentration (Cmax) and the prolongation time to reach Cmax in blood and other organs. Thus microencapsulated CPT may possess lower systemic toxicity and allow a reduction in dosage required to achieve therapeutic effectiveness. Results from initial human clinical trials underway by the authors and collaborators at MD Anderson Cancer Center, Houston, TX, are discussed. An interesting study by the authors, combination of aerosol delivered liposomal 9- nitrocamptothecin and polymer-p53 DNA formulation for inhibition of lung metastases in animal models is also discussed. Chand Khanna and David Vail from the National Cancer Institute, NIH, discuss dogs as models for studying aerosol delivery of formulations as well as treatment of naturally occurring cancers in dogs. The significant anatomic and physiological similarities between dogs and humans has resulted in dogs being used to define the safety profiles for novel cancer agents destined for use in human phase I clinical studies as well as preclinical evaluation of aerosol-based therapies. Dogs have been used to define particle distribution to the lung following inhalation of therapeutic aerosols. These studies provide in vivo validation of particle distribution and deposition hypotheses that are used to characterize inhaled aerosols based on particle size. The pharmacokinetics of delivered therapeutics in the dogs is reviewed and the extrapolations to humans discussed. The authors also discuss dog models for delivery of various chemotherapeutic drugs such as paclitaxel (PTX) and doxorubicin (DOX) for tumor models such as metastatic osteosarcoma and soft tissue sarcomas. In a review on aerosol delivery of genes, Charles Densmore at Baylor College of Medicine, Houston, TX, traces the rather checkered history of gene therapy, with special emphasis on aerosol delivery of genes for various pulmonary diseases such as lung cancer and cystic fibrosis. Various cationic lipid based delivery vectors and the problems encountered during nebulization are discussed. The main focus of the review is on an exciting new polymer, polyethylenimine (PEI), which has shown some very promising results in aerosol delivery of genes to the lungs. PEI-p53 DNA delivered by aerosol has demonstrated potent anti-cancer effects in various animal lung cancer models, and these are extensively reviewed. In B16-F10 melanoma in C57BL6 mice, aerosol delivery of PEI-p53 DNA inhibits lung metastases, but is rather ineffective in inhibiting established lung tumors. An interesting aspect of the study is the inhibition of extra-pulmonary metastases, although the localization of PEIp53 DNA particles as well as expression of p53 protein is localized to the lungs. Apoptosis and anti-angiogenesis effects of p53 explain the inhibition of pulmonary metastases, whereas the inhibition of extra-pulmonary metastases is primarily due to inhibition of angiogenesis by up regulation of thrombospondin-1 (TSP-1) and downregulation of vascular endothelial growth factor (VEGF). In the LM-6 human osteosarcoma (athymic nude mice) model, PEI-p53 DNA aerosol delivery potently inhibits the growth of established lung nodules. In each tumor model, twice a week delivery schedule using nebulization with 5% CO2 is effective in eliciting an anti-tumor response. A perspective on the future potential of aerosol gene therapy is also presented. A review on delivery of paclitaxel (Taxol) for potential treatment of lung cancer marks the end of this issue. Safe and efficient delivery of Taxol has been an issue ever since the drug was discovered, and aerosol modality provides at least one way to target the drug safely to the lungs. An overview of the drug, its chemical structure, mechanism of action, and various delivery vehicles and methodologies, with a discussion on the recent advances in aerosol delivery of the drug, are covered. As can be seen from the above reviews, the aerosol delivery of therapeutics holds tremendous promise for lung cancer. In spite of the promise, not many clinical studies are in progress using aerosol delivery of chemotherapeutic drugs or genes for pulmonary cancer. The ineffective delivery and side effects associated with aerosol delivery have been major drawbacks on the clinical applications. Recent advances have raised hopes for finally pushing the application of nebulized drugs beyond asthma and into pulmonary cancer and other diseases.

The lungs are common sites of involvement by primary and metastatic malignant disease. Patients with malignancies in the lung have limited treatment options and are usually not curable. Numerous investigators have studied the potential of delivering various therapeutic agents directly to the lungs and pulmonary lymphatics by nebulization. Most of the research involves the use of immunomodulatory strategies; a few aerosol studies of chemotherapy and gene therapy have also been conducted. Most of these studies have been conducted in animal models. A few human trials have also been completed. Results suggest that aerosol therapies have the potential to shrink pulmonary metastases of selected histologies, and that survival in selected patients with metastatic renal cell cancer may be prolonged. The approach to therapy of cancer in the lungs holds promise as a means to avoid systemic toxicity and obtain an improved therapeutic effect. Research is currently underway to address issues of local versus systemic toxicity, optimal drug delivery and selection of optimal drugs and schedules including outpatient aerosol therapy. Future issues in design of aerosol cancer treatment include identifying effective combinations of agents, schedules, and use of aerosol therapy at home as adjuvant therapy.

Lung cancer is the largest and the most common cause of cancer-related deaths worldwide. The cure rate for lung cancer remains lowest among all malignancies. The discovery of new chemical agents with activity in first onset and recurrent disease is crucial for advancing treatment of patients with pulmonary tumors. Camptothecins are known as inhibitors of topoisomerase I, one of the key enzymes for DNA replication and subsequent cell proliferation. Preclinical and clinical studies had shown that the camptothecins are active against lung cancer and other solid malignancies. In this paper, we review the status of camptothecin and derivatives for treatment of pulmonary cancers, including the development of new formulations and, particularly, novel aerosol routes of drug administration, and their application in combination therapy.

Pet dogs with naturally occurring cancers offer a novel opportunity for the study of both cancer biology and therapy. The following review will provide the rationale for the use of these spontaneous cancer models in translational research, particularly in the development of anticancer aerosols. A summary of work involving pet dogs with primary and metastatic cancers to the lung and the investigation of therapeutic chemotherapy and cytokine immunotherapy aerosols will be presented.

The long-term survival of lung cancer patients treated with conventional therapies (surgery, radiation therapy and chemotherapy) remains poor and has changed little in decades. The need for novel approaches remains high and gene therapy holds promise in this area. A number of genes have been shown in vitro, in animal studies and most recently, in human clinical trials, to have antitumor actions. However, a number of problems still exist and success in human patients to date has been marginal. Among the numerous considerations are the efficiency of delivery of the gene to the tumor or, if an indirect effect is the aim, possibly nontumor tissues, the efficiency and persistence of expression of the therapeutic gene, the specificity of the gene action against the tumor, potential toxic or pathogenic consequences of either the genes or the delivery vectors used, convenience of the therapy and how likely the therapy will compliment or complicate other conventional anticancer therapies. After the cloning of the cystic fibrosis gene, there was great interest in the noninvasive delivery of genes directly to the pulmonary surfaces by aerosol. Clearly, this approach could have application to some pulmonary cancers as well and most early efforts focused mainly on the use of nonviral vectors, primarily cationic lipids. Unfortunately, nebulization shear forces and inefficient pulmonary uptake and expression of plasmid DNA-cationic lipid formulations have generally resulted in a lack of therapeutic effect, so much of this work has diminished in recent years. Polyethyleneimine (PEI)-based formulations have proven stable during nebulization and result in nearly 100% efficient transfection throughout the airways and lung parenchyma. Therapeutic responses have been obtained in several animal lung tumor models when PEIbased formulations of p53 and other antitumor genes were delivered by aerosol. In addition, this mode of delivery seems to be associated with low toxicity and results in little or none of the immunostimulatory response typically associated with the delivery of bacterially produced plasmid DNA containing unmethylated CpG motifs, which has presented a challenge to repeated gene therapy via other modes of delivery. Other potential applications of PEI aerosol gene delivery include the treatment of asthma, lung alveolitis and fibrosis and a variety of monogeneic diseases such as cystic fibrosis and alpha-1-antitrypsin deficiency. In addition, a wide range of conditions treatable via genetic immunization could benefit from this approach to gene delivery as well.

Paclitaxel (PTX, Taxol) has revolutionized cancer treatment in the past decade and is recognized as one of the biggest advances in oncology medicine. In spite of the good clinical efficacy shown by PTX, there is still a growing need to achieve better safety and pharmacokinetic profile of PTX in patients. The standard delivery modalities of intravenous infusion result in multiple side effects, and targeting of the drug to specific areas within the body can result in better efficacy and lower toxicity. Aerosol delivery of therapeutic agents has the potential of localizing the drugs specifically to the lung tissue, with a comparable or better pharmacokinetics as compared to intravenous, oral or intraperitoneal delivery. Aerosol delivery of PTX has not been studied extensively, however, it holds immense potential for improving the efficacy against lung tumors. Early pre-clinical studies in mice and dogs have shown good promise, both for pharmacokinetics of PTX, safety and efficacy in lung cancer models. This review looks at the still developing approach of aerosol delivery of PTX for lung cancer, documents the progress so far and the future directions that can bring this approach to clinical reality.