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Clinical Cancer Research Vol. 7, 3258-3262, October 2001
© 2001 American Association for Cancer Research

Regular Articles

Paclitaxel Liposome Aerosol Treatment Induces Inhibition of Pulmonary Metastases in Murine Renal Carcinoma Model1

Nadezhda V. Koshkina2, J. Clifford Waldrep, Luz E. Roberts, Eva Golunski, Sara Melton and Vernon Knight

Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, Texas 77030


   ABSTRACT
Top
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
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.


   INTRODUCTION
Top
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The lungs are the common site of both metastases and primary neoplasia. The average lung cancer mortality is 90% and is the leading cause of cancer-related deaths in both men and women. One reason for the poor survival is that traditional methods of treatment, such as surgical resection, radiation, and chemotherapy have failed to eradicate lung cancer. Systemic chemotherapy has been used with little success because most current drugs delivered in this way are quickly destroyed or inactivated in blood and liver. Subsequently, not enough drug reaches the tumor at the therapeutic dose. Furthermore, drugs administered systemically may cause life-threatening systemic toxicity. An ideal chemotherapy would involve the administration of high concentrations of active agents directly and continuously to the target tissue to allow the maximum effect at the site of interest without adversely affecting other organs. For pulmonary diseases, aerosol technology has been developed to achieve this objective. This localized delivery method has a number of potential advantages over systemic delivery. Lungs provide a large absorptive surface for aerosol deposition and allow the drug to avoid the first-pass metabolic degradation (1, 2, 3) .

Our research group has developed experimental liposome aerosol formulations for pulmonary delivery of various active compounds, including the new potent anticancer lipophilic derivative of camptothecin 9-nitrocamptothecin (9NC). The aerosolized liposome 9NC formulation has proved effective against human cancer xenografts and experimental pulmonary metastases in mice at doses significantly lower than used by other routes of administration (4 , 5) . The human trials based on these results are under way.

PTX3 is the antineoplastic drug that demonstrated a therapeutic potential in lung cancer patients (6, 7, 8, 9) . PTX possesses a unique mechanism of action that differs from other anticancer drugs. It stabilizes microtubules by suppressing dynamic changes, affecting both growing and shortening, and leading to mitotic arrest (10 , 11) . In addition to the effects on mitosis, the broad antitumor activity of PTX may be the consequence of effects on the regulation of the cell cycle progression (12 , 13) . There may also be initiation of apoptosis (14 , 15) , alterations in the expression of gene products critical for tumor angiogenesis (16) , metastases (17) , or the host immune response (18) . In the clinic, PTX is administered by continuous i.v. infusion. However, PTX possesses a very low solubility in conventional aqueous vehicles, and the preparation approved for clinical use solubilizes PTX in mixture of polyethoxylated castor oil and ethanol. This vehicle may cause severe hypersensitivity reactions in humans (19 , 20) . Liposomes were found to be a viable alternative for the therapeutic use of PTX because of its improved toxicological and pharmacological characteristics (21 , 22) .

In the present report, we compared the effectiveness of PTX delivered to the lungs by liposome aerosol with i.v. administration of the same preparation. We also studied a therapeutic efficiency of PTX aerosol treatment on the growth of pulmonary metastases in the murine Renca model. We chose this model because renal cell carcinoma is characterized by a lack of early disease symptoms, which leads to a distant metastatic formation, including the lungs, in a majority of the patients at the time of diagnosis.


   MATERIALS AND METHODS
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Chemicals.
PTX was obtained from SuperGen, Inc, (San Ramon, CA). DLPC was purchased from Avanti Polar Lipids (Alabaster, AL). Organic solvents (HPLC grade) were obtained from Fisher Scientific. Sterile water for irrigation was purchased from Baxter Healthcare Corporation (Deerfield, IL).

Animals.
Female ICR and BALB/c mice (7–8 weeks old) were obtained from Harlan Sprague Dawley (Indianapolis, IN) and housed in standard cages with food and water provided ad libitum. Experiments were performed with the approval of the Institutional Animal Care and Use Committee.

Cell Culture and Animal Model.
The mouse Renca cell line was kindly provided by Dr. Robert Wiltrout, National Cancer Institute (Frederick, MD). The cells were maintained in vivo by serial renal passages according to the protocol provided by Dr. Wiltrout. Before in vivo implantation, Renca cells were cultured in vitro for two passages as described previously (23) . To induce pulmonary metastases, 100,000 cells were injected i.v. in 0.2 ml of saline via tail vein in syngeneic BALB/c mice.

Preparation of PTX-DLPC.
Liposomal formulation of PTX was prepared as described previously (24) . Briefly, stock solutions of DLPC and PTX were prepared in t-butanol. Aliquots of PTX and DLPC (1:10, w/w) were mixed and then frozen at -70°C and lyophilized overnight to dryness. The formulations were stored sealed at -20°C. Before use, the mixture was reconstituted with sterile water and vortexed until a homogeneous multilamellar liposomal suspension was obtained. The initial concentration of PTX in suspension before nebulization was 10 mg/ml.

The drug-liposome suspension was examined by microscopy under polarized light for the presence of drug crystals and by quasielastic light scattering with Nicomp Submicron Particle Sizer (Model 370, Santa Barbara, CA) for liposome particle size, before and after nebulization. A heterogeneous starting liposomal suspension had a wide size distribution (2.0–25.3 µm). During nebulization process, the shear forces generated by extrusion through the jet orifice reduced the liposome size to 0.23 ± 0.17 µm. Microscope analysis revealed that no crystallization of PTX was noticed before and after nebulization in reservoir.

Aerosol Drug Delivery and Dosage Calculation.
The treatment with aerosol of mice that bore pulmonary tumors was performed as previously described (4) . Briefly, an AERO-MIST jet nebulizer (cis-USA, Bedford, MA) was used to generate aerosol particles at the air flow rate of 10 liters/min. The aerosol particles were measured by Andersen Cascade Impactor and had a mass median diameter of 2.2 ± 0.2 µm (24) . Aerosol particles with this size will deposit predominantly in the lung periphery. Mice were placed in sealed plastic cages and exposed to aerosol for 30 min. The aerosol was generated with 5% CO2-enriched air obtained by mixing normal air and CO2 with a blender (Bird 3M, Palm Springs, CA) and the CO2 concentrations were calibrated with a Fluid Fyrite (Bacharach Inc., Pittsburgh, PA). The use of carbon dioxide increased pulmonary deposition of PTX ~3- to 4-fold (24) , and the total deposited dose during a 30-min inhalation of PTX-DLPC was 5 mg/kg.

Pharmacokinetic Studies.
ICR tumor-free mice were used for these studies. One group received 5 mg/kg PTX i.v. via the tail vein. The other group received the same dosage of PTX during a 30-min inhalation. At each time point, three mice were killed by exposure to Isoflurane, USP (Abbott Laboratories, Chicago, IL) and exsanguinated. The lungs were rapidly excised, weighed, frozen and stored at -70°C until analyzed.

The extraction procedure for PTX has been described previously (24) . Briefly, the sample was homogenized in 3 ml of ethylacetate in a mini-beadbeater. Homogenates were transferred to 10-ml glass tubes and centrifuged at 1000 x g for 10 min. The supernatant fraction was separated, and organic solvent was evaporated with air. The residue was reconstituted in 0.2 ml of methanol:acetonitrile (2:1, v/v), sonicated in a water-bath sonicator, and centrifuged at 1000 x g for 10 min. Supernatant fractions were analyzed by HPLC.

PTX was quantified by reverse-phase HPLC with monitoring on a Waters 486 UV absorbance detector at 227 nm (Waters, Milford, MA). All of the measurements were made at room temperature on Waters Nova-Pak C18 column (3.9 x 150 mm). The mobile phase was composed of 49% acetonitrile and 51% water.

In Vivo Antitumor Activity.
BALB/c mice were inoculated with tumor cells on day 0. On day 1, they were randomly divided into groups of 10 mice. One group of mice was left untreated, the second group of mice received 5 mg of PTX/kg by aerosol, and the third group inhaled blank liposomes (DLPC) at the dose equivalent to that in the same dose of PTX formulation. Mice were treated for 2 weeks. After that, they were killed by exposure to Isoflurane, USP, and exsanguination. Lungs were resected and weighed. After that, lungs were fixed in Bovin’s fixative for tumor enumeration and sizing. In survival studies, mice were getting treatment until they died.

Statistical Methods.
The statistical significance of differences between groups was calculated by Student’s t test. Evaluation of survival data was performed using Gehan’s test (Primer of Biostatistics 4.0 software). Ps < 0.05 were considered to be statistically significant.


   RESULTS
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Pulmonary Pharmacokinetics of PTX-DLPC Administered by Aerosol or i.v.
Fig. 1Citation shows the recovery of PTX from the lungs after single doses of 5 mg/kg PTX-DLPC given by aerosol or i.v. Observations of aerosol concentrations were started 5 min after the start of 30-min aerosol exposure. Measurements after i.v. treatment were begun 1 min after bolus injection of drug. Comparison of the area under the curve (AUC) revealed that in the lungs, AUC in the aerosol group was 26-fold higher than that after the i.v. injection (33.4 and 1.3 mg-h/g, respectively; P = 0.001, two-tailed t test). In the lungs at 1 min after i.v. treatment, there were 11.7 µg/g of PTX, but no other values exceeded 0.8 µg/g. The distribution half-life (t1/2{alpha}) for PTX administered by aerosol or i.v. was 0.71 h and 0.02 h, respectively, and lung concentrations after aerosol treatment during the 3-h period of observation ranged from 5.5 to 23.1 µg/g of tissue.



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  		Fig. 1. Pulmonary pharmacokinetics of PTX-DLPC administered by aerosol ({circ}) or i.v. (•). Mice inhaled the drug for 30 min; starting time, 0 (total deposited dose, 5 mg of PTX/kg). Bolus i.v. injection with 5 mg of PTX/kg was given into tail vein at time 0.

 
Treatment of Renca Pulmonary Tumors by PTX-DLPC Inhalation.
To study the in vivo activity of the liposomal preparation of PTX administered by aerosol, studies were performed in BALB/c mice with Renca pulmonary metastases. Mice received the first treatment at the dose of ~5 mg/kg by inhalation for 30 min 24 h after tumor inoculation. Additional treatments were given three times weekly at the same dosage and continued for 2 weeks. At that time, diffusely distributed, numerous, small tumor lesions were visible on lung surfaces. The antitumor effect of treatment was evaluated by the following parameters: lung weights, number of tumors, and median tumor size on the lung surface compared with untreated mice, or mice that received DLPC aerosol treatment only. In the PTX-DLPC group, lung weights were similar to the normal lung weights (179 ± 16 and 153 ± 19 mg, respectively; P > 0.05, two-tailed t test), whereas in untreated or DLPC-treated group, the lung weights were increased by 39 and 58%, respectively, compared with the normal lungs (Experiment 1; Table 1Citation ). The difference between lung weights for the PTX-DLPC group compared with those of the untreated or DLPC-treated groups was highly significant (P < 0.004, two-tailed t test). The mean number of tumor lesions on lung surfaces was similarly reduced in the treated group (P < 0.014, two-tailed t test) and the mean size of tumors was also less in the treated group. Fig. 2Citation is a photograph of the lungs of mice from the three experimental groups. The top row shows the heavily involved lungs of untreated mice; the middle row (DLPC only) shows involvement as great as that in the untreated mice; and the bottom row shows a clear reduction in the number of tumor lesions, although we did not achieve the complete elimination of tumors.


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  		Table 1 Effect of PTX liposome aerosol treatment on murine Renca metastases

 


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  		Fig. 2. Aerosol PTX-DLPC treatment of Renca pulmonary metastases in mice. Mice received injections i.v. of 100,000 Renca cells/mouse. Treatment was administered for 30 min, three times weekly for 2 weeks, starting 24 h after tumor inoculation. The top and middle rows, lungs of untreated and DLPC-only treated mice, respectively. The bottom row, lungs of mice treated with PTX-DLPC aerosol.

 
In another experiment, we decreased the frequency of treatments from three times per week to twice weekly for 17 days. The results showed a highly significant reduction in the lung weights (P < 0.0001, two-tailed t test) of PTX-DLPC treated mice compared with untreated animals (Experiment 2; Table 1Citation ). We did not observe a statistical difference in counts of tumor foci between the groups, despite the fact that median tumor size and range were significantly lower in the PTX-DLPC group compared with the untreated group (P < 0.013, two-tailed, t test). These data indicate that twice-weekly treatment is not as effective as the three-times-per-week treatment.

In a separate experiment, we further examined whether the inhalation of PTX would prolong the survival of mice bearing Renca lung metastases. Mice were inoculated with 100,000 cells into the tail vein. The treatment started on the next day and was given three times weekly. Another group of tumor-bearing mice was left untreated. The analysis of survival data (Fig. 3)Citation revealed a significant difference between treated and untreated groups (P = 0.035, Gehan’s test). Almost 40% of treated mice were alive on day 45, when all of the mice in the untreated group were dead. The mean survival time for treated mice was 43 ± 1 days; for untreated mice this value was 34 ± 1 days.



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  		Fig. 3. Survival time of mice bearing Renca pulmonary metastases treated with PTX-DLPC aerosol ({circ}) and untreated (•). Mice were inoculated with tumor cells and treated as described in the legend for Fig. 2Citation .

 

   DISCUSSION
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
In our previous studies, we have shown that the aerosol method of drug delivery, using 9NC, can be effectively used for experimental lung cancer therapy (5) . To increase the deposition efficiency of the drugs via aerosol, we used a modification by the addition of 5% CO2 to the breathing air. CO2-enriched air significantly increased the pulmonary concentration of anticancer drugs by about 3-fold compared with that achieved with ambient air (24) . In the present studies with this methodology, we found higher concentrations of PTX in the lungs than the concentration after i.v. injection. The clearance of inhaled PTX from the lungs was also slower.

In clinical trials, PTX is administered by continuous infusion because it provides prolonged exposure of the neoplastic cells to the drug. Liebmann et al. (25) had shown in vitro that the cytotoxicity of the drug was more dependent on increasing the duration of exposure than on increasing PTX concentrations. Aerosol delivery provides a continuous and direct exposure of the lungs to the drug. In our experiments, mice bearing Renca pulmonary metastases received ~5-mg/kg doses of PTX by inhalation three times weekly during 2 weeks. This dose was substantially lower than the most frequently used doses for i.v. or i.p. administration, >=20 mg/kg per injection (26, 27, 28) . Survival studies demonstrated prolonged mean survival of treated mice compared with untreated (up to 25%). The dose-dependence studies revealed that aerosol treatment three times weekly was more effective than twice per week. However, when we increased the frequency of treatments up to five times per week, we noticed an increased aggressiveness in mice behavior after 10–14 days of treatment, which might be explained in part by PTX-induced neurological toxicity (data not shown).

Although numerous preclinical studies have demonstrated the effectiveness of PTX in different tumor models, they used only invasive techniques, and the majority of the experiments were done with solid tumor xenografts. To our knowledge, this is the first study demonstrating the effectiveness of PTX aerosol treatment for local therapy of lung tumors in mice. However, although we did not achieve complete tumor growth arrest in this animal model, we believe that the effectiveness of this treatment may be further improved with combination therapy, using agents that have different mechanisms of action on cancer cells.


   FOOTNOTES
 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1 Supported by the Clayton Foundation for Research (Houston, TX). Presented in part at the 5th American Association for Cancer Research and Japanese Cancer Association Joint Conference, February 12–16, 2001, Maui, HI. Back

2 To whom requests for reprints should be addressed, at Department of Molecular Physiology and Biophysics, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX 77030. Fax: (713) 798-3475; E-mail: koshkina{at}bcm.tmc.edu Back

3 The abbreviation used are: PTX, paclitaxel; DLPC, dilauroylphosphatidylcholine; Renca, renal carcinoma cell line; HPLC, high-performance liquid chromatography. Back

Received 5/ 2/01; revised 7/23/01; accepted 7/23/01.


   REFERENCES
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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