According to the world cancer statistics, every year, it is estimated that there are about more than fourteen million people who are newly diagnosed with cancers, among these more than eight million patients with cancers will be projected to die. From the statistics, it is obvious that cancer will s...
According to the world cancer statistics, every year, it is estimated that there are about more than fourteen million people who are newly diagnosed with cancers, among these more than eight million patients with cancers will be projected to die. From the statistics, it is obvious that cancer will still be in among the deadliest diseases that we must cope with in the 21st century. One of the main reasons for such a high mortality rate is the poor targetability of the current DDS leading to low dose of chemotherapeutics delivered to cancerous sites and simultaneously causing severe advert side effects due to the off-target drugs. Therefore, novel delivery techniques are required to enhance the targetability of the DDS to effectively transport the therapeutics to the sites of interest and not to the normal sites. In addition, to gain the maximal therapeutic effects, it is necessary to trigger the release of the therapeutic agents from the DDS after reaching to the targets using external stimulus systems.
Among many types of particles that can be adopted to accommodate anticancer drugs, liposomes are widely used as the main drug carriers since they show superior advantages against their counterparts, such as biocompatibility, biodegradability, ability to encapsulate hydrophobic and/or hydrophilic drugs, and having “stealth” properties when decorated with polyethylene glycol that help the carriers avoid being cleared by mononuclear phagocytic system when administered into the body. In addition, many liposome-based drug delivery systems have already been approved by the FDA to be used for the treatment of several types of cancers. For these reasons, liposomes have been chosen as the main drug carriers of the developed DDS.
In this dissertation, different novel active targeted liposome-based DDS have been developed based on various strategies to improve the targetability and the therapeutic efficacy of the anticancer drugs. Briefly, in the first study, the author has utilized engineered nontoxic flagellar bacteria (Salmonella Typhimurium) that have chemotaxis towards cancer cells to help directionally drive paclitaxel-loaded liposomes (bacteriobots) kill the cells. It has been shown that due to the tumor targeting ability, the bacteriobots can kill the cancer cells much more effectively than the bacteria-free drug encapsulated liposomes. In the second study, the author has adopted immune cells (macrophages) to engulf paclitaxel-encapsulated magnetic nanoliposomes (cell-based microrobots) and aim to actively deliver the whole systems to the cancer sites using external electromagnetic actuating (EMA) system and the chemotaxis of the macrophages. Through the experiments, it has been confirmed that the microrobots can carry a sufficiently meaningful amount of drug to kill cancer cells in vitro. In the third study, using enhanced permeability and retention (EPR) effect and receptor mediated endocytosis (RME), the author has developed a docetaxel-loaded magnetic nanoliposome-based DDS that can actively target to CD44 receptors overexpressed cancer cells (MCF7, human origin breast cancer cells) and can increase the therapeutic effects of the system with the external NIR stimulus system to trigger the drug liberation. Finally, in the fourth study, the author has prepared a folate receptor targeting nanoliposome-based DDS, which are co-loaded with both doxorubicin and small size gold nanorods, that can selectively target folate receptors overexpressed mammary carcinoma (4T1) through EPR and RME with high interaction of folate ligand and folate receptors. In vitro cell experiments have proven that much higher cellular uptake can be achieved with the use of folate as targeting moiety of the DDS. And much more cells are killed by the targeting DDS in comparison with the nontargeting counterparts. Finally, in vivo experiments with 4T1 tumor-bearing-mice have confirmed that using the active targeting in combination with synergistic photothermal-chemotherapy, the newly developed DDS can effectively regress the tumor growth within two weeks after the treatment, whereas the other control groups can only delay the growing process.
Therefore, through the development of these above active DDS, the author believes that the dissertation has contributed the strategies that can help improve the disadvantages of the current DDS as well as has provided some suggestions for developing clinically better systems to combat against cancers.
According to the world cancer statistics, every year, it is estimated that there are about more than fourteen million people who are newly diagnosed with cancers, among these more than eight million patients with cancers will be projected to die. From the statistics, it is obvious that cancer will still be in among the deadliest diseases that we must cope with in the 21st century. One of the main reasons for such a high mortality rate is the poor targetability of the current DDS leading to low dose of chemotherapeutics delivered to cancerous sites and simultaneously causing severe advert side effects due to the off-target drugs. Therefore, novel delivery techniques are required to enhance the targetability of the DDS to effectively transport the therapeutics to the sites of interest and not to the normal sites. In addition, to gain the maximal therapeutic effects, it is necessary to trigger the release of the therapeutic agents from the DDS after reaching to the targets using external stimulus systems.
Among many types of particles that can be adopted to accommodate anticancer drugs, liposomes are widely used as the main drug carriers since they show superior advantages against their counterparts, such as biocompatibility, biodegradability, ability to encapsulate hydrophobic and/or hydrophilic drugs, and having “stealth” properties when decorated with polyethylene glycol that help the carriers avoid being cleared by mononuclear phagocytic system when administered into the body. In addition, many liposome-based drug delivery systems have already been approved by the FDA to be used for the treatment of several types of cancers. For these reasons, liposomes have been chosen as the main drug carriers of the developed DDS.
In this dissertation, different novel active targeted liposome-based DDS have been developed based on various strategies to improve the targetability and the therapeutic efficacy of the anticancer drugs. Briefly, in the first study, the author has utilized engineered nontoxic flagellar bacteria (Salmonella Typhimurium) that have chemotaxis towards cancer cells to help directionally drive paclitaxel-loaded liposomes (bacteriobots) kill the cells. It has been shown that due to the tumor targeting ability, the bacteriobots can kill the cancer cells much more effectively than the bacteria-free drug encapsulated liposomes. In the second study, the author has adopted immune cells (macrophages) to engulf paclitaxel-encapsulated magnetic nanoliposomes (cell-based microrobots) and aim to actively deliver the whole systems to the cancer sites using external electromagnetic actuating (EMA) system and the chemotaxis of the macrophages. Through the experiments, it has been confirmed that the microrobots can carry a sufficiently meaningful amount of drug to kill cancer cells in vitro. In the third study, using enhanced permeability and retention (EPR) effect and receptor mediated endocytosis (RME), the author has developed a docetaxel-loaded magnetic nanoliposome-based DDS that can actively target to CD44 receptors overexpressed cancer cells (MCF7, human origin breast cancer cells) and can increase the therapeutic effects of the system with the external NIR stimulus system to trigger the drug liberation. Finally, in the fourth study, the author has prepared a folate receptor targeting nanoliposome-based DDS, which are co-loaded with both doxorubicin and small size gold nanorods, that can selectively target folate receptors overexpressed mammary carcinoma (4T1) through EPR and RME with high interaction of folate ligand and folate receptors. In vitro cell experiments have proven that much higher cellular uptake can be achieved with the use of folate as targeting moiety of the DDS. And much more cells are killed by the targeting DDS in comparison with the nontargeting counterparts. Finally, in vivo experiments with 4T1 tumor-bearing-mice have confirmed that using the active targeting in combination with synergistic photothermal-chemotherapy, the newly developed DDS can effectively regress the tumor growth within two weeks after the treatment, whereas the other control groups can only delay the growing process.
Therefore, through the development of these above active DDS, the author believes that the dissertation has contributed the strategies that can help improve the disadvantages of the current DDS as well as has provided some suggestions for developing clinically better systems to combat against cancers.
주제어
#Drug delivery system liposome anticancer therapy
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