Polyalkylcyanoacrylate Nanoparticles loaded with chemotherapeutic drugs: Biodistribution, Anti-tumor efficacy and impact on tumor associated macrophages in breast and colorectal cancer models
1 Formål
Nanoparticles (NPs) based cancer therapy has acquired immense interest during the past years. NPs based drug delivery systems can deliver the drugs more specifically to the tumor. Thus, they offer improved efficacy and tumor targeting with reduced side effects and drug resistance, compared to conventional chemotherapeutics. In this study, we will use various polymeric polyalkylcyanoacrylate nanoparticles (PACA) with a polyethylene glycol (PEG) surface (which differ in their polymer composition), to encapsulate chemotherapeutic drugs. This project is a continuation of previous studies (FOTS approval no. 13581), where we obtained promising results with the drug Cabazitaxel (CBZ). A second drug to be tested is SN-38, which is the active component of the drug Irinotecan, commonly used in the treatment of colorectal cancer (CRC). SN-38 has also demonstrated promising results as an antibody-drug conjugate (sacituzumab govitecan) in triple negative breast cancer. Another drug candidate to be tested is RSL-3 which is a ferroptosis induced and recently proven to have ameliorating effects on different tumors in the pre-clinical phase.
In this study, we will be testing:
1) organ distribution of different PACA NPs in mice models of breast or colorectal cancer.
2) Pharmacokinetic study of RSL-3/PEBCA-RSL-3
3) MTD (Minimum toxic dose) study of RSL-3/PEBCA-RSL-3
4) Efficacy of CBZ /RSL-3/ SN-38 loaded NPs in mice models of breast cancer (CBZ NPs/RSL-3 NPs/SN-38 NPs) and CRC (SN-38 NPs).
5) Impact of empty or drug loaded NPs on immune cell infiltration in the proposed models.
2 Skadevirkninger
Biodistribution study involves intravenous injection of NPs, and in vivo imaging after providing anesthesia in tumor bearing mice. This may cause mild stress to the animals.
Pharmcokinetic study involves single i.v. injection of tolerated dose of RSL-3/PEBCA-RSL-3 and collecting blood samples at different time points to determine the plasma concentration of the drug. This may cause mild stress to the animals.
MTD study involves systematic escalation of doses or repeated dosing of RSL-3/PEBCA RSL-3. We expect that that we can detect any early signs of intolerance by closely monitoring the animals and will not allow any mice to reach severe distress and death.
Mice model of breast cancer will be implanted tumors orthotopically, into their mammary fat pad, or subcutaneously near to the mammary fat pad. This involves surgical procedure, with prior anesthesia and analgesia. Mice model of colon cancer will be implanted tumors subcutaneously on the flank. The growing tumors may cause discomforts and may impair normal movement when the tumors are large. But we will not allow any severe tumor burden, the animals will be euthanized beforehand.
The animals will receive treatment with free drug or drug loaded NPs. This can result in loss of body weight and the animals may experience discomforts. But, we will be administering a well tolerated dose of drug which was optimized from previous studies.
3 Forventet nytteverdi
The study will provide a direct pre-clinical analysis of these different NPs, which forms the basis for their future clinical applications. It may also provide leads to develop improved forms of these NPs for cancer therapy.
4 Antall dyr og art
We apply for a total of 1096 mice.
5 Hvordan etterleve 3R
We aim to replace and reduce the number of animals and will always try to refine the procedures. The efficacy of cancer treatment and the distribution of nanoparticles and cancer drugs in an organism are complex and there are no validated alternative techniques available till date to test these effects in an efficient manner. The number of mice proposed is kept as low as possible, but high enough not to compromise the scientific quality of experiment and statistical analysis of the results.
Nanoparticles (NPs) based cancer therapy has acquired immense interest during the past years. NPs based drug delivery systems can deliver the drugs more specifically to the tumor. Thus, they offer improved efficacy and tumor targeting with reduced side effects and drug resistance, compared to conventional chemotherapeutics. In this study, we will use various polymeric polyalkylcyanoacrylate nanoparticles (PACA) with a polyethylene glycol (PEG) surface (which differ in their polymer composition), to encapsulate chemotherapeutic drugs. This project is a continuation of previous studies (FOTS approval no. 13581), where we obtained promising results with the drug Cabazitaxel (CBZ). A second drug to be tested is SN-38, which is the active component of the drug Irinotecan, commonly used in the treatment of colorectal cancer (CRC). SN-38 has also demonstrated promising results as an antibody-drug conjugate (sacituzumab govitecan) in triple negative breast cancer. Another drug candidate to be tested is RSL-3 which is a ferroptosis induced and recently proven to have ameliorating effects on different tumors in the pre-clinical phase.
In this study, we will be testing:
1) organ distribution of different PACA NPs in mice models of breast or colorectal cancer.
2) Pharmacokinetic study of RSL-3/PEBCA-RSL-3
3) MTD (Minimum toxic dose) study of RSL-3/PEBCA-RSL-3
4) Efficacy of CBZ /RSL-3/ SN-38 loaded NPs in mice models of breast cancer (CBZ NPs/RSL-3 NPs/SN-38 NPs) and CRC (SN-38 NPs).
5) Impact of empty or drug loaded NPs on immune cell infiltration in the proposed models.
2 Skadevirkninger
Biodistribution study involves intravenous injection of NPs, and in vivo imaging after providing anesthesia in tumor bearing mice. This may cause mild stress to the animals.
Pharmcokinetic study involves single i.v. injection of tolerated dose of RSL-3/PEBCA-RSL-3 and collecting blood samples at different time points to determine the plasma concentration of the drug. This may cause mild stress to the animals.
MTD study involves systematic escalation of doses or repeated dosing of RSL-3/PEBCA RSL-3. We expect that that we can detect any early signs of intolerance by closely monitoring the animals and will not allow any mice to reach severe distress and death.
Mice model of breast cancer will be implanted tumors orthotopically, into their mammary fat pad, or subcutaneously near to the mammary fat pad. This involves surgical procedure, with prior anesthesia and analgesia. Mice model of colon cancer will be implanted tumors subcutaneously on the flank. The growing tumors may cause discomforts and may impair normal movement when the tumors are large. But we will not allow any severe tumor burden, the animals will be euthanized beforehand.
The animals will receive treatment with free drug or drug loaded NPs. This can result in loss of body weight and the animals may experience discomforts. But, we will be administering a well tolerated dose of drug which was optimized from previous studies.
3 Forventet nytteverdi
The study will provide a direct pre-clinical analysis of these different NPs, which forms the basis for their future clinical applications. It may also provide leads to develop improved forms of these NPs for cancer therapy.
4 Antall dyr og art
We apply for a total of 1096 mice.
5 Hvordan etterleve 3R
We aim to replace and reduce the number of animals and will always try to refine the procedures. The efficacy of cancer treatment and the distribution of nanoparticles and cancer drugs in an organism are complex and there are no validated alternative techniques available till date to test these effects in an efficient manner. The number of mice proposed is kept as low as possible, but high enough not to compromise the scientific quality of experiment and statistical analysis of the results.