Biomedical subjects

J C Waldrep

Publications and source records attributed to J C Waldrep.

At least 19 recordsLinked to original sources

PubMed2003

Camptothecins and lung cancer: improved delivery systems by aerosol.

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.

Administration, Inhalation↗

PubMed2002

Growth inhibition of established B16-F10 lung metastases by sequential aerosol delivery of p53 gene and 9-nitrocamptothecin.

Growth inhibition of established tumor metastases in the lungs poses a difficult challenge for most clinical settings in spite of extensive multi-modality approaches. Aerosol delivery of drugs and genes holds promise for the treatment of disseminated lung metastases, since aerosol delivery can target the lungs specifically and uniformly. We previously demonstrated that aerosol delivery of dilauroylphosphatidylcholine liposome formulation of 9-nitrocamptothecin (9NC-DLPC) inhibits B16-F10 melanoma lung metastases. Aerosol delivery of polyethleneimine-p53 DNA (PEI-p53) complexes results in a similar anti-tumor effect in the B16-F10 model. In both these previous studies, the protocols were designed to inhibit development of lung metastases. In this study we demonstrate, using the B16-F10 melanoma lung metastasis model, that sequential aerosol delivery of PEI-p53 and 9NC-DLPC acts additively to inhibit growth of established B16-F10 tumor metastases in the lungs. Mice injected with B16-F10 cells and treated with a combination of 9NC-DLPC (twice weekly) and PEI-p53 (once weekly) aerosol complexes starting on day 11 after tumor inoculation, exhibited a highly significant (P < 0.01) reduction in the number of visible tumor foci as compared with untreated mice or mice treated with either single agent alone, or with a combination of 9NC and a control plasmid. There was a highly significant reduction in the tumor burden, as well as the lung weights for the 9NC and p53 combination group (P < 0.001 as compared with other groups). Moreover, the doses of p53 gene and 9NC in the combination group were reduced at least two-fold as compared with our previous single agent studies, but still achieved significant tumor inhibition. Furthermore, the sequential aerosol delivery of p53 and 9NC lead to a 30-40% increase in the mean survival time of these mice, as compared with animals in different control groups. The data suggest that the combination of 9NC and p53 gene delivered by aerosol is an attractive strategy for growth inhibition of established tumor metastases in the lungs.

Aerosols↗

PubMed2001

Transgene expression in mouse airway epithelium by aerosol gene therapy with PEI-DNA complexes.

Gene therapy targeted at the respiratory epithelium holds therapeutic potential for diseases such as cystic fibrosis and alpha-1 anti-trypsin deficiency. A variety of approaches such as intranasal or intratracheal instillation and aerosol delivery have been utilized to target genes to the airways. Polyethylenimine (PEI), a linear or branched polycationic polymer, has been used for delivery of genes to various organs. In this study, using fluorescein isothiocyanate (FITC)-labeled branched PEI, we initially examined the localization of PEI in the lungs after aerosol delivery to Balb/C mice. Further, after aerosol delivery of PEI-CAT DNA, in situ immunostaining for chloramphenicol acetyl transferase (CAT) protein was used to localize the transgene expression within the lungs. Immunohistochemistry for CAT, as well as localization of FITC-labeled PEI, revealed that after aerosol delivery, the PEI-DNA complexes deposit and subsequently transfect most of the epithelial cells in the conducting airways (including the peripheral airways). High levels of CAT were detected at 24 h after aerosol exposure and significant CAT expression was detected in the lungs up to 28 days after a single aerosol exposure. The data suggest that aerosol delivery of PEI-DNA complexes could be effective for the treatment of pulmonary diseases such as cystic fibrosis and alpha-1 anti-trypsin deficiency.

Administration, Inhalation↗

PubMed2001

Improved respiratory delivery of the anticancer drugs, camptothecin and paclitaxel, with 5% CO2-enriched air: pharmacokinetic studies.

PURPOSE: To increase pulmonary deposition of anticancer liposome aerosols in mice by modulation of respiratory physiology through the addition of 5% CO2 to the air source used to generate the aerosols. Breathing CO2-enriched aerosol increases pulmonary ventilation with concurrent increased deposition of inhaled particles. METHODS: Dilauroylphosphatidylcholine liposome formulations of two anticancer drugs, paclitaxel (PTX) and camptothecin (CPT), were investigated. The aerosol droplet size was measured using an Andersen cascade impactor. Drug concentrations in aerosol droplet fractions and tissues were determined by HPLC analysis. ICR mice were exposed to each liposome aerosol for 30 min. For each drug, one group of mice inhaled the drug-liposome aerosol generated with a mixture of 5% CO2 in air and another group inhaled the drug-liposome aerosols produced with normal air. Tissue distribution and pharmacokinetics were determined for both drug delivery systems. RESULTS: Significantly higher concentrations of PTX and CPT were found in organs of mice exposed to 5% CO2-air aerosols compared to organs of mice exposed to normal air aerosols. The highest concentrations of drug were detected in the lungs and were two- to fourfold higher with 5% CO2-air aerosols than with aerosols generated with normal air. Higher concentrations were also detected in liver, spleen, kidneys, blood, and brain. CONCLUSION: 5% CO2 enrichment of air increased respiratory tract deposition of inhaled aerosol particles containing PTX and CPT.

Administration, Inhalation↗

PubMed2001

Growth suppression of established human osteosarcoma lung metastases in mice by aerosol gene therapy with PEI-p53 complexes.

Lung metastases are a frequent complication of osteosarcoma and a treatment that would reduce the severity of this complication would be of great benefit to patients. We have used a formulation consisting of polyethyleneimine (PEI) and a p53 gene administered in aerosol to treat established lung micrometastases as a model of human osteosarcoma in nude mice. The SAOS-LM6 cell line, a metastatic derivative of the p53 null SAOS-2 line, expresses high levels of p53 protein after in vitro transfection with PEI-p53 complexes as determined by ELISA, and transfection with both p53wt and the p53 variant, p53-CD(1-366) in vitro, results in a marked inhibition of SAOS-LM6 cell proliferation. Aerosol delivery of plasmid DNA containing either the p53 gene or a p53-CD(1-366) variant gene formulated with PEI to mice resulted in highly significant reductions in the numbers and size of tumors (P<.001), the total number of tumor foci in the lungs (P<.001) and the size of individual tumor nodules in treated animals compared to untreated, PEI only-treated and PEI-CAT-treated control animals. The different tissues examined did not reveal any signs of toxicity or inflammation after repeated exposure to PEI-DNA. The aerosol delivery of PEI-based formulations of p53 or synthetic p53 variant genes represents a promising new strategy for the treatment of established human osteosarcoma lung metastases. The noninvasive nature of aerosol delivery coupled with low toxicity also make this therapeutic approach potentially appropriate for combination therapy with either radio- or chemotherapy.

Administration, Inhalation↗

PubMed2001

Pulmonary cytokine responses associated with PEI-DNA aerosol gene therapy.

Pulmonary gene therapy with nonviral vectors delivered by instillation or intravenously has typically been associated with co-induction of cytokine responses attributed to the CpG motifs in the bacterial plasmid. Alternative delivery systems are being developed to circumvent the cytokine responses to the plasmid. Aerosol delivery of polyethylenimine--DNA (PEI-DNA) complexes leads to localized, high levels of transgene expression in the lungs. In this study, we show that PEI-DNA aerosol delivery is also associated with induction of tumor necrosis factor alpha (TNF-alpha) and interleukin 1 beta (IL-1 beta) in the lung and bronchoalveolar lavage fluid (BALF). However, there is no increase in the serum levels of these cytokines. The levels of these cytokines peak at 5--8 h after aerosol exposure for lung tissue, and at 24 h for BALF. However, the levels detected are much lower than those observed when PEI-DNA complexes, guanidinium--cholesterol: dioleoylphosphatidyl--ethanolamine liposome--DNA (BGTC:DOPE--DNA) complexes or 1,2-dioleoyl-sn-glycero-3-trimethylammonium--propane--cholesterol:DNA (DOTAP-Chol:DNA) complexes were delivered intravenously. Also, the lung cytokine levels were higher when BGTC:DOPE--DNA complexes were delivered by aerosol to the mice. Although the mechanism remains to be elucidated, the data suggest that aerosol exposure to PEI--DNA complexes can achieve high levels of transgene expression in the lungs without inducing high levels of cytokine responses.

Administration, Inhalation↗

PubMed2001

Aerosol characterization of nebulized intranasal glucocorticoid formulations.

Inhaled glucocorticoids (GCs) are the mainstay of long-term therapy for asthma. The lack of suitable preparations in the United States has induced clinicians to use intranasal (IN) GC formulations as "nebulizer suspensions" for off-label therapy. However, no data are available regarding aerosol production and characteristics. The aim of this study was to characterize drug outputs and aerodynamic profiles of four nebulized IN GC formulations with further analysis of flunisolide (Flu), and to test the influence of different delivery system/formulation combinations. The aerodynamic profiles and drug outputs were determined by impaction and chemical analysis. The solution output was determined by the gravimetric technique. Triamcinole acetonide (TAA), fluticasone propionate (Flut), beclomethasone dipropionate (Bec), and Flu (550, 500, 840, and 250 microg, respectively) diluted to 4 mL with saline solution were tested with the Sidestream (SID) and Aero-Tech II (AT2) nebulizers. Subsequently, Flu was tested with four additional nebulizers (Pari LC + [PARI] Acorn II, Hudson T Up-draft II, and Raindrop). All the aerosols were heterodisperse and had a particle size range optimal for peripheral airway deposition (1.85 to 3.67 microm). Flu had the highest drug output in the respirable range (22.8 and 20.3 microg/min with the AT and SID, respectively). Flu was 5-11 times more efficiently nebulized than the other formulations tested. No differences were detected in the solution outputs (0.25 to 0.3 mL/min). In subsequent testing of Flu, the PARI, AT, and SID showed the best performances. The LC+ achieved the highest drug and solution output (27.4 microg/min and 0.89 mL/min, respectively). In conclusion, Flu showed the best aerosol performance characteristics. These data do not endorse the off-label utilization of nebulized IN GC, but underscores the importance of in vitro testing before selecting any formulation/nebulizer combinations for clinical use.

Administration, Inhalation↗

PubMed2001

Metering performance of several metered-dose inhalers with different spacers/holding chambers.

Metered-dose inhalers (MDI) are routinely used to administer inhaled antiasthma drugs. Actuation-inhalation coordination problems are overcome and systemic side effects are reduced by using spacers/holding chambers (SP/HCHs). Many of these devices do not allow the use of the manufacturer's actuator. The objectives of this study were (a) to investigate the effect of the interaction of eight MDI products with four different SP/HCHs on their metering performance (MP); and (b) to test the hypothesis whether the MP obtained with a SP/HCH and a given drug (MDI) can be extrapolated to other MDIs, even for members of its particular drug class. The procedure outlined in The United States Pharmacopeia-The National Formulary was used (determination of canister weight changes after actuation). The SP/HCH tested were Aerochamber, Inspirease, and ACE. The MDIs tested were salmeterol xinafoate; albuterol with chlorofluorocarbons and 1,1,1,2-tetrafluoroethane as propellants; cromolyn sodium; nedocromil sodium; flunisolide; beclomethasone dipropionate; and fluticasone propionate. Only flunisolide-Inspirease presented an unacceptable MP. Although within the acceptable limits, the MP varied significantly between the following MDI-SP/HCH combinations: Optihaler-fluticasone propionate and Optihaler-cromolyn sodium < to Aerochamber-fluticasone propionate and Aerochamber-cromolyn sodium (p = 0.0015 and p = 0.0007, respectively); and Inspirease-flunisolide and Optihaler-flunisolide < Aerochamber flunisolide (p = 0.003 and p = 0.005, respectively). MP did not significantly vary when albuterol with chlorofluorocarbons or 1,1,1,2-tetrafluoroethane as propellants, salmeterol xinafoate, beclomethasone dipropionate, and nedocromil sodium were attached to any of the SP/HCHs studied. Our results emphasize the capital importance of choosing the right combination of MDI and SP/HCH for aerosol delivery. The MP obtained with a drug and a SP/HCH cannot be expected to be similar for other MDIs, even for members of its drug class. These data also suggest the need for regulatory agencies to approve an MDI to be used only with the SP/HCHs tested.

Administration, Inhalation↗

PubMed2001

Paclitaxel liposome aerosol treatment induces inhibition of pulmonary metastases in murine renal carcinoma model.

The present studies were undertaken to evaluate the pulmonary pharmacokinetics and therapeutic efficacy of paclitaxel (PTX) administered by aerosol. PTX was encapsulated into dilauroylphosphatidylcholine liposomal formulations (PTX-DLPC). The deposition and clearance of PTX-DLPC in the lungs administered by aerosol or i.v. at comparative doses was performed, and PTX was quantitatively determined in tissue extracts by high-performance liquid chromatography analysis. The murine renal carcinoma (Renca) pulmonary metastases model was used to determine the therapeutic effect of drug formulation administered by aerosol. PTX-DLPC aerosols were generated with the Aero-Mist jet nebulizer (cis-USA). The most effective schedule of treatment was when mice inhaled the drug for 30 min 3 days per week. There was a significant reduction of the lung weights and reduced number of visible tumor foci on the lung surfaces of mice treated with PTX aerosol (P < 0.004 and P < 0.01, respectively) compared with control groups. Inhalation of PTX-DLPC also led to prolonged survival in mice inoculated with Renca cells. The results of the present studies demonstrate the therapeutic potential of aerosol technology for lung cancer treatment.

Administration, Inhalation↗

PubMed2000

Aerosol delivery of robust polyethyleneimine-DNA complexes for gene therapy and genetic immunization.

Aerosol delivery of plasmid DNA to the lungs offers the possibility of direct application of gene preparations to pulmonary surfaces as a means of treating a variety of genetic pulmonary disorders. However, the process of jet nebulization rapidly degrades naked DNA, viral vectors, and many lipid-based formulations. While complexing DNA with cationic lipids has been shown to significantly stabilize plasmid DNA, losses of biological activity often occur during nebulization, severely limiting the efficiency of aerosol delivery of many such complexes. In conjunction with the design of aerosol delivery systems appropriate for DNA delivery, we have developed formulations using polyethyleneimine (PEI, a polycationic polymer) and DNA that result in a high level of pulmonary transfection (10- to 100-fold greater than many cationic lipids) and are stable during nebulization. In addition, these PEI-based formulations exhibit a high degree of specificity for the lungs. The properties of PEI-based formulations that make them resistant to nebulization and efficient as DNA delivery vectors for pulmonary sites have been investigated. Potential applications of this technology, including the use of aerosolized PEI-DNA for genetic immunization, are discussed.

Aerosols↗

PubMed2000

Enhanced gene expression in mouse lung after PEI-DNA aerosol delivery.

Aerosol gene delivery to the pulmonary system has vast potential for many diseases, including cystic fibrosis and lung cancer. We recently reported that polyethyleneimine (PEI), a cationic polymer, holds promise as a gene delivery vector for transfection in lung by aerosol. To further optimize the gene expression in the lung by aerosol, we utilized 5% CO(2) in air for the nebulization of PEI-DNA complexes. Five percent CO(2)-in-air gave a threefold higher gene expression compared to normal air using the chloramphenicol acetyl transferase (CAT) reporter gene delivered by Aerotech II nebulizer. The delivery of DNA by PEI was dose dependent with the highest expression obtained when 2 mg of DNA in 10 ml was nebulized at a PEI nitrogen:DNA phosphate (N:P) ratio of 10:1. The optimal N:P ratio for lung transfection was found to be between 10:1 and 20:1 using the CAT and luciferase reporter genes. The time-course studies showed the highest expression at 24 h after aerosol delivery and 40-50% of peak level was detectable even after a week. Tissue distribution indicates the expression to be specific to the lung with no detectable expression in any other tissue examined. Histological and biochemical analysis of lungs revealed no evidence of acute inflammation.

Aerosols↗

PubMed2000

Inhibition of experimental lung metastasis by aerosol delivery of PEI-p53 complexes.

Mutations in the p53 tumor suppressor gene and the pathways mediated by the p53 protein are common in many human cancers. Replacement of functional p53 by gene therapy is a potential way of combating these cancers and the associated drug resistance and tumor growth. Aerosol delivery of genes is a noninvasive way of targeting genes to the lung for gene therapy. Here we demonstrate, using a murine melanoma lung metastasis model, that aerosol delivery of polyethyleneimine-p53 (PEI-p53) complexes inhibits the growth of lung metastasis. A significantly reduced number of visible foci were observed in C57BL/6 mice injected with B16-F10 melanoma and treated with PEI-p53 complexes by aerosol for 3 weeks at twice a week. Fifty percent of the mice in the PEI-p53-treated group exhibited no visible tumor foci. There was a significant reduction in the lung weights of p53-treated mice (P < 0.01) compared to control groups. The tumor burden was also significantly lower (P < 0.001) in mice treated with PEI-p53 complexes. No extrapulmonary metastasis was observed in the groups treated with PEI-p53 complexes compared to 50% of the mice in control groups, which showed metastasis to lymph nodes in the neck or abdomen. Treatment with PEI-p53 aerosol also led to about a 50% increase in the mean length of survival of the mice injected with B16-F10 cells. These data suggest that delivery of the p53 gene by aerosol using PEI as the gene delivery vector can inhibit the growth of lung metastasis.

Administration, Inhalation↗

PubMed2000

9-Nitrocamptothecin liposome aerosol treatment of human cancer subcutaneous xenografts and pulmonary cancer metastases in mice.

The purpose of this study was to test the anticancer properties of the water-insoluble derivative of camptothecin, 9-nitrocamptothecin (9NC), administered in a liposome formulation (L-9NC) in aerosol to mice with subcutaneous xenografts of three human cancers and in mice with murine melanoma and human osteosarcoma pulmonary metastases. The drug was formulated with dilauroylphosphatidylcholine and nebulized in particle sizes of 1.2-1.6 microns mass median aerodynamic diameter and a geometric standard deviation of 2.0. The aerosol was generated with the nebulizer flowing at 10 l/min and delivered to mice in sealed plastic cages or in a nose-only exposure chamber. Aerosol was administered for 15 min to 2 hr daily, delivering deposited doses in the respiratory tract of 8.1-306.7 micrograms of 9NC/kg. With subcutaneous tumors, growth was greatly inhibited or tumors were undetectable after several weeks of treatment. We also showed that oral dosage with L-9NC had no detectable effect on cancer growth, and thus the benefit from aerosol treatment was due to pulmonary deposition and not the larger fraction of drug deposited in the nose of mice during aerosol treatment which is promptly swallowed. Intramuscular L-9NC in slightly larger doses than given in the aerosol had detectable anticancer activity, but it was significantly less than in mice receiving the drug by aerosol. With metastatic pulmonary cancers, treated animals showed highly significantly less cancer growth than control animals. L-9NC aerosol showed a major therapeutic benefit in the treatment of subcutaneous human cancer xenografts in nude mice, suggesting that cancers at systemic sites might be responsive to this treatment. In addition, the strong anticancer effect of L-9NC aerosol on pulmonary metastases offers a therapeutic approach for treatment of pulmonary cancers. Thus, L-9NC aerosol may have applicability in the treatment of cancers throughout the body.

Aerosols↗

PubMed1999

Differential subcellular localization of the survival motor neuron protein in spinal cord and skeletal muscle.

To compare the expression pattern of the survival motor neuron (SMN) protein in spinal cord and skeletal muscle, we generated a sheep polyclonal antibody against a bacterially expressed human SMN-fusion protein. On Western blots, the affinity purified anti-SMN antibody recognized a approximately 38 kDa protein band in extracts prepared from the mouse skeletal muscle, spinal cord, and brain that co-migrated with the bacterially expressed SMN protein. In immunohistochemical studies, the anti-SMN antibody labeled mostly the cytoplasm of the motor neurons in the anterior horn of mouse spinal cord. In contrast, predominant uniform labeling of the nuclei was observed in the mouse skeletal muscle. Thus, our results for the first time demonstrate that the SMN protein is differentially localized in mouse spinal cord and skeletal muscle.

Animals↗

PubMed1999

Anticancer effect of 9-nitrocamptothecin liposome aerosol on human cancer xenografts in nude mice.

PURPOSE: To test the anticancer properties of the water-insoluble derivative of camptothecin, 9-nitrocamptothecin (9-NC) against human breast, colon and lung cancer xenografts in nude mice when administered in liposome aerosol. METHODS: The drug was formulated with dilauroylphosphatidylcholine and nebulized in a particle size of 1.6 microm +/- 2.0 mass median diameter to deliver doses of usually less than 200 microg/kg daily, 5 days per week. 9-NC liposome aerosols were generated with a Aerotech II nebulizer (CIS-USA) flowing at 101/min from a compressed air source and delivered to mice in sealed plastic cages or in a nose-only exposure chamber. RESULTS: Tumor growth was greatly reduced or tumors were undetectable after several weeks of treatment. Colon tumor was least responsive. 9-NC was better than the parent compound, camptothecin, also water-insoluble, tested by aerosol in a similar liposomal preparation. Equivalent doses of 9-NC liposome preparations administered by mouth were substantially without effect while there was some effect, but limited, of the liposome preparation given intramuscularly. CONCLUSIONS: 9-NC liposome aerosol was strikingly effective in the treatment of three human cancer xenografts growing subcutaneously over the thorax in nude mice at doses much smaller than those traditionally used in mice administered by other routes.

Animals↗

PubMed1999

Distribution of camptothecin after delivery as a liposome aerosol or following intramuscular injection in mice.

PURPOSE: The plant alkaloid camptothecin (CPT) has shown significant antitumor activity against a wide variety of human tumors xenografted in nude mice. In previous studies we have found that administration of dilauroylphosphatidylcholine (DLPC) liposome aerosols containing 9-nitrocamptothecin (9-NC) inhibits the growth of human breast, colon and lung cancer xenografts. The purpose of this study was to analyze the pharmacokinetics and tissue distribution of inhaled CPT formulated in DLPC liposomes. METHODS: C57BL/6 mice with subcutaneous Lewis lung carcinoma, Swiss nu/nu mice with human lung carcinoma xenografts and BALB/c mice without tumors were used for pharmacokinetic studies of CPT administered as a liposome aerosol and BALB/c mice were given CPT intramuscularly. RESULTS: After 30 min inhalation of CPT liposome aerosol, drug was deposited in the lungs (310 ng/g) and was followed promptly by the appearance of high concentrations in the liver (192 ng/g) and with lesser amounts appearing in other organs. Drug concentration in the brain was 61 ng/g. After intramuscular injection of CPT dissolved in DMSO, drug was released from the site of injection very slowly and accumulated mainly in the liver (136 ng/g). Only trace amounts appeared in the lungs (2-4 ng/g). These results demonstrate a prompt pulmonary and later systemic distribution of CPT following liposome aerosol administration. CONCLUSIONS: The substantial concentrations of CPT in lungs and other organs following inhalation of liposome aerosol suggest the possible benefit of it and of its more active derivative, 9-NC, in the treatment of lung, liver, kidney and brain cancer in humans.

Aerosols↗

PubMed1999

Pharmacokinetics of liposomal aerosolized cyclosporine A for pulmonary immunosuppression.

BACKGROUND: The results of pulmonary transplantation are compromised by acute and chronic rejection. We hypothesized that a liposomal form of aerosolized cyclosporine A (CsA) would be selectively deposited and concentrated in the lungs. The theoretical advantage of this therapy is selective pulmonary immunosuppression with prolonged utilization. METHODS: Eighteen dogs were endotracheally intubated; aerosolized liposomal CsA was administered for 15 min. CsA levels were measured in whole blood, lung, trachea, heart, kidney, liver, and spleen at various times after treatment. RESULTS: The lung rapidly absorbs aerosolized liposomal CsA; other organs have much lower concentrations. The retention of pulmonary CsA delivered by liposome aerosol is approximately 120 min in this model. CONCLUSIONS: Aerosolized liposomal CsA is selectively deposited and concentrated in the lungs; other organs absorb less CsA.

Aerosols↗

PubMed1998

New aerosol drug delivery systems for the treatment of immune-mediated pulmonary diseases.

In the lung, unchecked immune responses mediated predominantly by T-lymphocytes and concurrent inflammation can lead to the development of different pathological conditions such as parenchymal disease, interstitial fibrosis, hypersensitivity pneumonitis, bronchiolitis obliterans and bronchiolar asthma. Targeted modulation of uncontrolled T-cell activation and inhibition of cytokine production within different pulmonary compartments is the challenge for the development of novel methods for immunotherapeutic intervention. Utilization of aerosol technology for pulmonary drug delivery represents new potential opportunities for therapeutic application for such immune-mediated pulmonary diseases. For targeted aerosol pulmonary drug delivery, continuous-flow jet nebulizers have several advantages over metered dose or dry powder inhalers since they are the simplest and most effective for aerosol droplet deposition into the peripheral lung tissues. At the present, the major limitations for targeted pulmonary immunosuppression through effective utilization of nebulizer technology has been the conspicuous lack of suitable formulations. The development of liposomal formulations compatible with aerosol delivery with jet nebulizers has expanded the potential for more effective utilization with an array of potent and effective immunosuppressive drugs. For pulmonary therapy, the utilization of liposomes for aerosol delivery has many potential advantages, including universal carrier suitability for most lipophilic drugs, aqueous compatibility, sustained pulmonary release or depot and intracellular delivery. Drug liposomes may also prevent local irritation in the lung, and increase potency with reduced systemic toxicity. Successful utilization of potent immunosuppressive drugs, like cyclosporin, tacrolimus (FK-506), rapamycin, mycophenolate and budesonide, in a variety of immunopathological conditions for other indications demonstrates their potential efficacy for the treatment of many different immune-mediated pulmonary diseases. The route of delivery to the pulmonary tissues can potentially limit adverse effects and markedly affect localized immunosuppressive activity in the lung. Combination of liposomal formulations with topical aerosol delivery to the central and peripheral lung tissues has expanded potential for more effective utilization with these lipophilic immunosuppressive (and antiinflammatory) drugs. Synergistic combinations can also be developed for localized and sustained delivery of therapeutic drug concentrations within the lung to provide multisite immunosuppression. Drug liposome aerosol technology represents one readily available approach for more effective therapeutic intervention in the lung using cyclosporin, FK-506, rapamycin, mycophenolate, budesonide and other lipophilic drugs.

Journal Article↗