Synthesis and characterization of novel reformulated bioactive paclitaxel complexes and considerations for administration via inhalation method for targeted lung cancer treatment
Location
Moultrie, GA
Start Date
4-5-2022 1:00 PM
End Date
4-5-2022 4:00 PM
Description
Introduction
Paclitaxel (Taxol) earned a reputation for being history’s best-selling cancer medication. The issue with paclitaxel (PAC) and other taxanes is their poor water solubility, and as a result, low bioavailability and serum lifetime. To be of clinical use, paclitaxel relies on the addition of polyoxyethylated castor oil as a solubilizing agent. This additive presents the issue of toxicity, which results in non-compliance for many patients. To overcome the challenges of poor solubility and toxicity, new drug delivery systems have been explored. A focus is placed on lung cancer due to it causing the most deaths of all cancer types. Inhaled chemotherapy has not been extensively studied but offers a solution for patients with lung cancers who experience toxicity because of traditional treatment.
Objectives
The objectives of this study are to 1. Discuss anticancer activity of two novel drugs: Cu5Fe5PAC and (CUPAC)5GLU12DALB (CPGD) and 2. Evaluate the ability of paclitaxel to be vaporized for inhalation therapy.
Methods
The first part of this study focuses on activity of the two novel paclitaxel drugs. The first drug contains paclitaxel complexed with copper and iron (Cu5Fe5PAC). The second drug contains paclitaxel complexed with copper, glucose, and denatured albumin ([CUPAC]5GLU12DALB). Antitumor activity of both drugs is compared to pure paclitaxel using the National Cancer Institute’s (NCI) sixty in-vitro cell line panel that tests against nine cancer types. The NCI data provides GI50, LC50 and TGI values for the drugs tested. A two-sample t-test (CI= 95%) was utilized to evaluate any significant difference in values for each drug compared to paclitaxel. The second part of the study evaluates the vaporization capability of paclitaxel. The device used is the Volcano Medic II by Storz and Bickel. A combination of propylene glycol/vegetable glycerin (PG/VG) is used to carry the drugs into the vapor form. Each PG/VG ratio contains 1 part ethanol with dissolved drug. The standard recommended combination is a 3:1 ratio of propylene glycol/glycerin. The Volcano Medic II contains temperature control settings. The first trial using this device compares various drug combinations at a standard temperature (200oC) and PG/VG combination (3:1). The second trial evaluates the vaporization capability of pure paclitaxel at various temperatures (from 160-210oC) and PG/VG combinations (3:1; 1:3; 1:1). Each flask containing the vapor product is weighed, and the flasks with the highest weight increase were evaluated via LC-MS.
Results
The GI50 values demonstrate a drug’s cytostatic ability. The GI50 values for Cu5Fe5PAC closely resemble those of pure paclitaxel, but the drug is not as effective (PAC average= -7.71; Cu5Fe5PAC average= -7.38). For CPGD, the GI50 values vary more, with an average of -6.56. T-test results show a significant difference in the GI50 values of PAC compared to Cu5Fe5PAC (p-value= 0.041) and CPGD (p-value= 4.99 x 10-21). The LC50 values indicate the cytotoxic ability of the drugs. The LC50 values for CPGD demonstrate overall lower cytotoxic concentrations than Cu5Fe5PAC (Cu5Fe5PAC average= -4.48; CPGD average= -5.02). CPGD also demonstrates a better cytotoxic effect than PAC with an average of -4.69. T-test results indicate a significant difference between LC50 values of PAC compared to Cu5Fe5PAC (p-value= 1.00 x 10-4) and CPGD (5.84 x 10-9). The TGI values indicate the concentration resulting in total inhibition of growth. PAC is the most successful overall, with an average of -5.39 as compared to Cu5Fe5PAC at -4.54 and CPGD at -5.20. T-test results indicated a significant difference in TGI values between PAC and Cu5Fe5PAC (p-value= 3.35 x 10-11). Values for PAC compared to CPGD were not considered significantly different (p-value= 0.171). The first Volcano Medic trial at standard temperature and PG/VG combination demonstrated a vapor yield as follows: Ethanol > Ethanol + PAC > Ethanol + Cu5Fe5PAC. The second trial at variable temperature and PG/VG combination demonstrated that the combinations with the most vapor yield are 3:1 PG/VG at 170oC, 1:3 PG/VG at 200oC, and 1:1 PG/VG at 210oC. Included in LC-MS testing was the 3:1 PG/VG combination at 200oC since it was used as the standard in earlier trials. The intensity of paclitaxel per LC-MS is as follows: 1:3 PG/VG at 200oC (intensity= 1.95 x 100,000); 3:1 PG/VG at 200oC (intensity= 0.92 x 100,000); 1:1 PG/VG at 210oC (intensity= 2.05 x 10,000); and 3:1 PG/VG at 170oC (intensity= 2.05 x 10,000). These are compared to a pure paclitaxel spectrum with an intensity of 1.4 x 1,000,000. This trial demonstrated that a higher viscosity solution (1:2 PG/VG) results in higher vapor and drug yield.
Conclusion
The two drugs synthesized, Cu5Fe5PAC and (CUPAC)5GLU12DALB, both show anticancer activity in vitro that is comparable to that of pure PAC. The components complexed with paclitaxel in each drug offer advantages over pure paclitaxel, including decreased toxicity, increased water solubility, and increased bioavailability. The full efficacy of the drugs must be evaluated through in vivo testing. The vaporization trials demonstrate the ability of paclitaxel to be carried over into the vapor phase. The higher viscosity liquid was able to carry over the large paclitaxel molecule more easily. It is predicted that this behavior is likely to be seen with vaporization of other drugs as well. Inhaled chemotherapy has not been extensively studied but offers a solution for patients with lung cancers who experience toxicity because of traditional treatment. Studies will need to be conducted in the future to evaluate all safety aspects of inhaled chemotherapy drug administration.
Embargo Period
5-31-2022
Synthesis and characterization of novel reformulated bioactive paclitaxel complexes and considerations for administration via inhalation method for targeted lung cancer treatment
Moultrie, GA
Introduction
Paclitaxel (Taxol) earned a reputation for being history’s best-selling cancer medication. The issue with paclitaxel (PAC) and other taxanes is their poor water solubility, and as a result, low bioavailability and serum lifetime. To be of clinical use, paclitaxel relies on the addition of polyoxyethylated castor oil as a solubilizing agent. This additive presents the issue of toxicity, which results in non-compliance for many patients. To overcome the challenges of poor solubility and toxicity, new drug delivery systems have been explored. A focus is placed on lung cancer due to it causing the most deaths of all cancer types. Inhaled chemotherapy has not been extensively studied but offers a solution for patients with lung cancers who experience toxicity because of traditional treatment.
Objectives
The objectives of this study are to 1. Discuss anticancer activity of two novel drugs: Cu5Fe5PAC and (CUPAC)5GLU12DALB (CPGD) and 2. Evaluate the ability of paclitaxel to be vaporized for inhalation therapy.
Methods
The first part of this study focuses on activity of the two novel paclitaxel drugs. The first drug contains paclitaxel complexed with copper and iron (Cu5Fe5PAC). The second drug contains paclitaxel complexed with copper, glucose, and denatured albumin ([CUPAC]5GLU12DALB). Antitumor activity of both drugs is compared to pure paclitaxel using the National Cancer Institute’s (NCI) sixty in-vitro cell line panel that tests against nine cancer types. The NCI data provides GI50, LC50 and TGI values for the drugs tested. A two-sample t-test (CI= 95%) was utilized to evaluate any significant difference in values for each drug compared to paclitaxel. The second part of the study evaluates the vaporization capability of paclitaxel. The device used is the Volcano Medic II by Storz and Bickel. A combination of propylene glycol/vegetable glycerin (PG/VG) is used to carry the drugs into the vapor form. Each PG/VG ratio contains 1 part ethanol with dissolved drug. The standard recommended combination is a 3:1 ratio of propylene glycol/glycerin. The Volcano Medic II contains temperature control settings. The first trial using this device compares various drug combinations at a standard temperature (200oC) and PG/VG combination (3:1). The second trial evaluates the vaporization capability of pure paclitaxel at various temperatures (from 160-210oC) and PG/VG combinations (3:1; 1:3; 1:1). Each flask containing the vapor product is weighed, and the flasks with the highest weight increase were evaluated via LC-MS.
Results
The GI50 values demonstrate a drug’s cytostatic ability. The GI50 values for Cu5Fe5PAC closely resemble those of pure paclitaxel, but the drug is not as effective (PAC average= -7.71; Cu5Fe5PAC average= -7.38). For CPGD, the GI50 values vary more, with an average of -6.56. T-test results show a significant difference in the GI50 values of PAC compared to Cu5Fe5PAC (p-value= 0.041) and CPGD (p-value= 4.99 x 10-21). The LC50 values indicate the cytotoxic ability of the drugs. The LC50 values for CPGD demonstrate overall lower cytotoxic concentrations than Cu5Fe5PAC (Cu5Fe5PAC average= -4.48; CPGD average= -5.02). CPGD also demonstrates a better cytotoxic effect than PAC with an average of -4.69. T-test results indicate a significant difference between LC50 values of PAC compared to Cu5Fe5PAC (p-value= 1.00 x 10-4) and CPGD (5.84 x 10-9). The TGI values indicate the concentration resulting in total inhibition of growth. PAC is the most successful overall, with an average of -5.39 as compared to Cu5Fe5PAC at -4.54 and CPGD at -5.20. T-test results indicated a significant difference in TGI values between PAC and Cu5Fe5PAC (p-value= 3.35 x 10-11). Values for PAC compared to CPGD were not considered significantly different (p-value= 0.171). The first Volcano Medic trial at standard temperature and PG/VG combination demonstrated a vapor yield as follows: Ethanol > Ethanol + PAC > Ethanol + Cu5Fe5PAC. The second trial at variable temperature and PG/VG combination demonstrated that the combinations with the most vapor yield are 3:1 PG/VG at 170oC, 1:3 PG/VG at 200oC, and 1:1 PG/VG at 210oC. Included in LC-MS testing was the 3:1 PG/VG combination at 200oC since it was used as the standard in earlier trials. The intensity of paclitaxel per LC-MS is as follows: 1:3 PG/VG at 200oC (intensity= 1.95 x 100,000); 3:1 PG/VG at 200oC (intensity= 0.92 x 100,000); 1:1 PG/VG at 210oC (intensity= 2.05 x 10,000); and 3:1 PG/VG at 170oC (intensity= 2.05 x 10,000). These are compared to a pure paclitaxel spectrum with an intensity of 1.4 x 1,000,000. This trial demonstrated that a higher viscosity solution (1:2 PG/VG) results in higher vapor and drug yield.
Conclusion
The two drugs synthesized, Cu5Fe5PAC and (CUPAC)5GLU12DALB, both show anticancer activity in vitro that is comparable to that of pure PAC. The components complexed with paclitaxel in each drug offer advantages over pure paclitaxel, including decreased toxicity, increased water solubility, and increased bioavailability. The full efficacy of the drugs must be evaluated through in vivo testing. The vaporization trials demonstrate the ability of paclitaxel to be carried over into the vapor phase. The higher viscosity liquid was able to carry over the large paclitaxel molecule more easily. It is predicted that this behavior is likely to be seen with vaporization of other drugs as well. Inhaled chemotherapy has not been extensively studied but offers a solution for patients with lung cancers who experience toxicity because of traditional treatment. Studies will need to be conducted in the future to evaluate all safety aspects of inhaled chemotherapy drug administration.
Comments
Winner of PCOM South Georgia Biomedical Sciences Student Research Award