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Yechezkel Barenholz - One of the best experts on this subject based on the ideXlab platform.
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Effect of major tumor metabolites on release of doxorubicin from Doxil – implications for precision nano-medicine.
Precision Nanomedicine, 2020Co-Authors: Liza Silverman, Yechezkel BarenholzAbstract:Our previous studies demonstrate that ammonia induces doxorubicin release from Doxil® in a concentration-dependent manner. Because ammonia that results from glutaminolysis is continu-ously generated in tumors at high enough concentration to induce doxorubicin release of Doxil in tumors, this may explain why doxorubicin release in interstitial tumor fluids is much faster and higher than in the plasma, in which release is minimal. This unique activity of tumor ammo-nia may explain, at least in part, the therapeutic efficacy of Doxil, which in practice does not re-lease doxorubicin in animal and human plasma. Our current study aims to evaluate if tumor-specific metabolites other than ammonia, such as lactate and pyruvate, are also involved in dox-orubicin release from Doxil. Also, we studied levels of ammonia in other mouse organs. Our data shows that these other metabolites do not affect doxorubicin release. Furthermore, using the Metabolic gEne RApid Visualizer database (MERAV), we computationally explored the relation-ships of glutaminase (GLS) 1 and 2, glutamate dehydrogenase (GLUD)1 and 2, as well as gluta-mine transporters regulating the glutaminolysis levels found in different cancers. These glutami-nolysis levels could not be achieved without the upregulation of glutamine transporters. Indeed, our queries to MERAV showed that SLC38A1, SLC38A2, and especially SLC38A6, are upregu-lated in cancerous tissues. We discuss how the information on the upregulation of enzymes re-lated to glutaminolysis could be used for “precision medicine” to determine if Doxil is an ap-propriate choice for a specific cancer patient. Our computational exploration shows that glutami-nolysis is heightened in some cancerous tissues as compared to their normal counterparts, but not in all cases. It would be possible and perhaps advantageous to test individual patient tissues to determine glutaminolysis, and therefore likely, ammonium levels in cancerous tissues, and to use this to ascertain if Doxil would be a good treatment choice.
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effect of major tumor metabolites on release of doxorubicin from Doxil implications for precision nano medicine
Precision Nanomedicine, 2020Co-Authors: Liza Silverman, Yechezkel BarenholzAbstract:Our previous studies demonstrate that ammonia induces doxorubicin release from Doxil® in a concentration-dependent manner. Because ammonia that results from glutaminolysis is continu-ously generated in tumors at high enough concentration to induce doxorubicin release of Doxil in tumors, this may explain why doxorubicin release in interstitial tumor fluids is much faster and higher than in the plasma, in which release is minimal. This unique activity of tumor ammo-nia may explain, at least in part, the therapeutic efficacy of Doxil, which in practice does not re-lease doxorubicin in animal and human plasma. Our current study aims to evaluate if tumor-specific metabolites other than ammonia, such as lactate and pyruvate, are also involved in dox-orubicin release from Doxil. Also, we studied levels of ammonia in other mouse organs. Our data shows that these other metabolites do not affect doxorubicin release. Furthermore, using the Metabolic gEne RApid Visualizer database (MERAV), we computationally explored the relation-ships of glutaminase (GLS) 1 and 2, glutamate dehydrogenase (GLUD)1 and 2, as well as gluta-mine transporters regulating the glutaminolysis levels found in different cancers. These glutami-nolysis levels could not be achieved without the upregulation of glutamine transporters. Indeed, our queries to MERAV showed that SLC38A1, SLC38A2, and especially SLC38A6, are upregu-lated in cancerous tissues. We discuss how the information on the upregulation of enzymes re-lated to glutaminolysis could be used for “precision medicine” to determine if Doxil is an ap-propriate choice for a specific cancer patient. Our computational exploration shows that glutami-nolysis is heightened in some cancerous tissues as compared to their normal counterparts, but not in all cases. It would be possible and perhaps advantageous to test individual patient tissues to determine glutaminolysis, and therefore likely, ammonium levels in cancerous tissues, and to use this to ascertain if Doxil would be a good treatment choice.
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Doxebo (doxorubicin-free Doxil-like liposomes) is safe to use as a pre-treatment to prevent infusion reactions to PEGylated nanodrugs.
Journal of controlled release : official journal of the Controlled Release Society, 2019Co-Authors: Yaelle Bavli, Janos Szebeni, Rivka Cohen, Ilan Winkler, Bing Mae Chen, Steve R. Roffler, Yechezkel BarenholzAbstract:The increasing use in the last decade of PEGylated nanodrugs such as Doxil® has seen a rise in the number of associated occurrences of hypersensitivity reactions (HSRs). These reactions (also called infusion reactions or IR), can range from harmless symptoms to life-threatening reactions. Current means to prevent IR include the prophylactic use of antihistamines and steroids, but they cannot ensure total prevention. We previously showed that an intravenous injection of doxorubicin-free Doxil-like PEGylated nano-liposomes (Doxebo) prior to Doxil treatment suppresses Doxil-induced complement activation-related pseudoallergy (CARPA) in pigs, a model of human hypersensitivity reactions to Doxil. However, in order to use Doxebo to prevent Doxil-induced IR, we have to prove its safety and that it does not affect Doxil's performance. Here we show that Doxebo itself does not have toxic effects on the host or tumor, and it does not interfere with Doxil's antitumor activity in mice. Blood, microscopic and macroscopic organ evaluation of rats after repeated administration confirm the lack of intrinsic adverse effect of Doxebo. Likewise, the repeated injection of Doxebo before Doxil did not impact Doxil's pharmacokinetics in plasma and therefore does not cause accelerated blood clearance (ABC). Taken together with our previous publications, these data suggest that the injection of Doxebo prior to Doxil administration can help protect against Doxil-induced IR without adversely affecting treatment efficacy and safety.
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Understanding the Role of Anti-PEG Antibodies in the Complement Activation by Doxil in Vitro.
Molecules (Basel Switzerland), 2018Co-Authors: Barry W. Neun, Janos Szebeni, Yechezkel Barenholz, Marina A. DobrovolskaiaAbstract:Infusion reactions (IRs) are common immune-mediated side effects in patients treated with a variety of drug products, including, but not limited to, nanotechnology formulations. The mechanism of IRs is not fully understood. One of the best studied mechanisms of IRs to nanomedicines is the complement activation. However, it is largely unknown why some patients develop reactions to nanomedicines while others do not, and why some nanoparticles are more reactogenic than others. One of the theories is that the pre-existing anti-polyethylene glycol (PEG) antibodies initiate the complement activation and IRs in patients. In this study, we investigated this hypothesis in the case of PEGylated liposomal doxorubicin (Doxil), which, when used in a clinical setting, is known to induce IRs; referred to as complement activation-related pseudoallergy (CARPA) in sensitive individuals. We conducted the study in vitro using plasma derived from C57BL/6 mice and twenty human donor volunteers. We used mouse plasma to test a library of well-characterized mouse monoclonal antibodies with different specificity and affinity to PEG as it relates to the complement activation by Doxil. We determined the levels of pre-existing polyclonal antibodies that bind to PEG, methoxy-PEG, and PEGylated liposomes in human plasma, and we also assessed complement activation by Doxil and concentrations of complement inhibitory factors H and I in these human plasma specimens. The affinity, specificity, and other characteristics of the human polyclonal antibodies are not known at this time. Our data demonstrate that under in vitro conditions, some anti-PEG antibodies contribute to the complement activation by Doxil. Such contribution, however, needs to be considered in the context of other factors, including, but not limited to, antibody class, type, clonality, epitope specificity, affinity, and titer. In addition, our data contribute to the knowledge base used to understand and improve nanomedicine safety.
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Cardinal Role of Intraliposome Doxorubicin-Sulfate Nanorod Crystal in Doxil Properties and Performance.
ACS omega, 2018Co-Authors: Xiaohui Wei, Dima Shamrakov, Sioma Nudelman, Sivan Peretz-damari, Einat Nativ-roth, Oren Regev, Yechezkel BarenholzAbstract:The uniqueness of Doxil can be attributed, to a large extent, to its intraliposomal doxorubicin-sulfate nanorod crystal. We re-examine these nanocrystal features and their mechanism of the formatio...
Alexander M.m. Eggermont - One of the best experts on this subject based on the ideXlab platform.
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Addition of low-dose tumor necrosis factor-α to systemic treatment with STEALTH liposomal doxorubicin (Doxil) improved anti-tumor activity in osteosarcoma-bearing rats
Anti-cancer drugs, 2005Co-Authors: Saske Hoving, Ann L.b. Seynhaeve, Sandra T. Van Tiel, Alexander M.m. Eggermont, Timo L.m. Ten HagenAbstract:Improved efficacy of Doxil (STEALTH liposomal doxorubicin) compared to free doxorubicin has been demonstrated in the treatment of several tumor types. We have shown that addition of low-dose tumor necrosis factor (TNF) to systemic Doxil administration dramatically improved tumor response in the highly vascularized rat soft tissue sarcoma BN175. Whether a similar enhanced efficacy can be achieved in less vascularized tumors is uncertain. We therefore examined the effect of systemic administration of Doxil in combination with low-dose TNF in intermediate vascularized osteosarcoma-bearing rats (ROS-1). Small fragments of the osteosarcoma were implanted s.c. in the lower limb. Treatment was started when the tumors reached an average diameter of 1 cm. Rats were treated with five i.v. injections at 4-day intervals with Doxil or doxorubicin and TNF. Systemic treatment with Doxil resulted in a better tumor growth delay than free doxorubicin, but with progressive diseases in all animals. The 3.5-fold augmented accumulation of Doxil compared to free doxorubicin presumably explains the enhanced tumor regression. Addition of low-dose TNF augmented the anti-tumor activity of Doxil, although no increased drug uptake was found compared to Doxil alone. In vitro studies showed that ROS-1 is sensitive to TNF, but systemic treatment with TNF alone did not result in a tumor growth delay. Furthermore, we demonstrated that treatment with Doxil alone or with TNF resulted in massive coagulative necrosis of tumor tissue. In conclusion, combination therapy of Doxil and low-dose TNF seems attractive for the treatment of highly vascularized tumors, but also of intermediate vascularized tumors like the osteosarcoma.
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Low‐dose tumor necrosis factor‐α augments antitumor activity of stealth liposomal doxorubicin (Doxil®) in soft tissue sarcoma‐bearing rats
International journal of cancer, 2000Co-Authors: Timo L.m. Ten Hagen, Ann L.b. Seynhaeve, Sandra T. Van Tiel, Alexander H. Van Der Veen, P.t.g.a. Nooijen, Alexander M.m. EggermontAbstract:It has previously been demonstrated in the setting of an isolated limb perfusion that application of high-dose TNF-α in combination with chemotherapy (melphalan, doxorubicin) results in strong synergistic antitumor effects in both the clinical and preclinical settings. In this study, we demonstrate that systemic administration of low-dose TNF-α augments the antitumor activity of a liposomal formulation of doxorubicin (Doxil®). Addition of TNF-α to a Doxil® regimen, which by itself induced some tumor growth delay, resulted in massive necrosis and regression of tumors. Furthermore, we could demonstrate a significant increase of liposomal drug in the tumor tissue when TNF-α had been co-administered. Administration of TNF-α augmented Doxil® accumulation only after repeated injections, whereas accumulation of free doxorubicin was not affected by TNF-α. Drug levels in the tumor interstitium appeared crucial as intracellular levels of free or liposome-associated doxorubicin were not increased by TNF-α. Therefore, we hypothesize that low-dose TNF-α augments leakage of liposomal drug into the tumor interstitium, explaining the observed improved antitumor effects. Regarding the effects of systemic administration of low doses of TNF-α, these findings may be important for enhanced tumor targeting of various liposomal drug formulations. Int. J. Cancer 87:829–837, 2000. © 2000 Wiley-Liss, Inc.
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low dose tumor necrosis factor α augments antitumor activity of stealth liposomal doxorubicin Doxil in soft tissue sarcoma bearing rats
International Journal of Cancer, 2000Co-Authors: Timo Ten L M Hagen, Ann L.b. Seynhaeve, Sandra T. Van Tiel, Alexander H. Van Der Veen, P.t.g.a. Nooijen, Alexander M.m. EggermontAbstract:It has previously been demonstrated in the setting of an isolated limb perfusion that application of high-dose TNF-α in combination with chemotherapy (melphalan, doxorubicin) results in strong synergistic antitumor effects in both the clinical and preclinical settings. In this study, we demonstrate that systemic administration of low-dose TNF-α augments the antitumor activity of a liposomal formulation of doxorubicin (Doxil®). Addition of TNF-α to a Doxil® regimen, which by itself induced some tumor growth delay, resulted in massive necrosis and regression of tumors. Furthermore, we could demonstrate a significant increase of liposomal drug in the tumor tissue when TNF-α had been co-administered. Administration of TNF-α augmented Doxil® accumulation only after repeated injections, whereas accumulation of free doxorubicin was not affected by TNF-α. Drug levels in the tumor interstitium appeared crucial as intracellular levels of free or liposome-associated doxorubicin were not increased by TNF-α. Therefore, we hypothesize that low-dose TNF-α augments leakage of liposomal drug into the tumor interstitium, explaining the observed improved antitumor effects. Regarding the effects of systemic administration of low doses of TNF-α, these findings may be important for enhanced tumor targeting of various liposomal drug formulations. Int. J. Cancer 87:829–837, 2000. © 2000 Wiley-Liss, Inc.
Timo L.m. Ten Hagen - One of the best experts on this subject based on the ideXlab platform.
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Intact Doxil is taken up intracellularly and released doxorubicin sequesters in the lysosome: Evaluated by in vitro/in vivo live cell imaging
Journal of controlled release : official journal of the Controlled Release Society, 2013Co-Authors: Ann L.b. Seynhaeve, Saske Hoving, Bilyana M. Dicheva, Gerben A. Koning, Timo L.m. Ten HagenAbstract:Doxil, also known as Caelyx, is an established liposomal formulation of doxorubicin used for the treatment of ovarian cancer, sarcoma and multiple myeloma. While showing reduced doxorubicin related toxicity, Doxil does not greatly improve clinical outcome. To become biologically active, doxorubicin needs to be released from its carrier. Uptake and breakdown of the liposomal carrier and subsequent doxorubicin release is not fully understood and in this study we explored the hypothesis that Doxil is taken up by tumor cells and slowly degraded intracellularly. We investigated the kinetics of liposomal doxorubicin (Doxil) in vitro as well as in vivo by measuring cytotoxic effect, intracellular bioavailability and fate of the carrier and its content. To prevent fixation artifacts we applied live cell imaging in vitro and intravital microscopy in vivo. Within 8h after administration of free doxorubicin, 26% of the drug translocated to the nucleus and when reaching a specific concentration killed the cell. Unlike free doxorubicin, only 0.4% of the doxorubicin added as liposomal formulation entered the nucleus. Looking at the kinetics, we observed a build-up of nuclear doxorubicin within minutes of adding free doxorubicin. This was in contrast to Doxil showing slow translocation of doxorubicin to the nucleus and apparent accumulation in the cytoplasm. Observations made with time-lapse live cell imaging as well as in vivo intravital microscopy revealed the liposomal carrier colocalizing with doxorubicin in the cytoplasm. We also demonstrated the sequestering of liposomal doxorubicin in the lysosomal compartment resulting in limited delivery to the nucleus. This entrapment makes the bioavailable concentration of Doxil-delivered doxorubicin significantly lower and therefore ineffective as compared to free doxorubicin in killing tumor cells.
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Addition of low-dose tumor necrosis factor-α to systemic treatment with STEALTH liposomal doxorubicin (Doxil) improved anti-tumor activity in osteosarcoma-bearing rats
Anti-cancer drugs, 2005Co-Authors: Saske Hoving, Ann L.b. Seynhaeve, Sandra T. Van Tiel, Alexander M.m. Eggermont, Timo L.m. Ten HagenAbstract:Improved efficacy of Doxil (STEALTH liposomal doxorubicin) compared to free doxorubicin has been demonstrated in the treatment of several tumor types. We have shown that addition of low-dose tumor necrosis factor (TNF) to systemic Doxil administration dramatically improved tumor response in the highly vascularized rat soft tissue sarcoma BN175. Whether a similar enhanced efficacy can be achieved in less vascularized tumors is uncertain. We therefore examined the effect of systemic administration of Doxil in combination with low-dose TNF in intermediate vascularized osteosarcoma-bearing rats (ROS-1). Small fragments of the osteosarcoma were implanted s.c. in the lower limb. Treatment was started when the tumors reached an average diameter of 1 cm. Rats were treated with five i.v. injections at 4-day intervals with Doxil or doxorubicin and TNF. Systemic treatment with Doxil resulted in a better tumor growth delay than free doxorubicin, but with progressive diseases in all animals. The 3.5-fold augmented accumulation of Doxil compared to free doxorubicin presumably explains the enhanced tumor regression. Addition of low-dose TNF augmented the anti-tumor activity of Doxil, although no increased drug uptake was found compared to Doxil alone. In vitro studies showed that ROS-1 is sensitive to TNF, but systemic treatment with TNF alone did not result in a tumor growth delay. Furthermore, we demonstrated that treatment with Doxil alone or with TNF resulted in massive coagulative necrosis of tumor tissue. In conclusion, combination therapy of Doxil and low-dose TNF seems attractive for the treatment of highly vascularized tumors, but also of intermediate vascularized tumors like the osteosarcoma.
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Lack of efficacy of Doxil® in TNF-α-based isolated limb perfusion in sarcoma-bearing rats
British journal of cancer, 2004Co-Authors: Timo L.m. Ten Hagen, Saske Hoving, G Ambagtsheer, S T Van Tiel, A. M. M. EggermontAbstract:Here we show that Doxil® has minimal antitumour activity in the isolated limb perfusion (ILP) setting and its activity was not enhanced by the addition of tumour necrosis factor (TNF). Doxil® accumulation in tumour tissue was low and also not augmented by TNF. In contrast, activity of free conventional doxorubicin was enhanced by TNF. We conclude that application of Doxil® in a TNF-based ILP is not a useful alternative to free conventional doxorubicin or melphalan.
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Low‐dose tumor necrosis factor‐α augments antitumor activity of stealth liposomal doxorubicin (Doxil®) in soft tissue sarcoma‐bearing rats
International journal of cancer, 2000Co-Authors: Timo L.m. Ten Hagen, Ann L.b. Seynhaeve, Sandra T. Van Tiel, Alexander H. Van Der Veen, P.t.g.a. Nooijen, Alexander M.m. EggermontAbstract:It has previously been demonstrated in the setting of an isolated limb perfusion that application of high-dose TNF-α in combination with chemotherapy (melphalan, doxorubicin) results in strong synergistic antitumor effects in both the clinical and preclinical settings. In this study, we demonstrate that systemic administration of low-dose TNF-α augments the antitumor activity of a liposomal formulation of doxorubicin (Doxil®). Addition of TNF-α to a Doxil® regimen, which by itself induced some tumor growth delay, resulted in massive necrosis and regression of tumors. Furthermore, we could demonstrate a significant increase of liposomal drug in the tumor tissue when TNF-α had been co-administered. Administration of TNF-α augmented Doxil® accumulation only after repeated injections, whereas accumulation of free doxorubicin was not affected by TNF-α. Drug levels in the tumor interstitium appeared crucial as intracellular levels of free or liposome-associated doxorubicin were not increased by TNF-α. Therefore, we hypothesize that low-dose TNF-α augments leakage of liposomal drug into the tumor interstitium, explaining the observed improved antitumor effects. Regarding the effects of systemic administration of low doses of TNF-α, these findings may be important for enhanced tumor targeting of various liposomal drug formulations. Int. J. Cancer 87:829–837, 2000. © 2000 Wiley-Liss, Inc.
Ann L.b. Seynhaeve - One of the best experts on this subject based on the ideXlab platform.
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intact Doxil is taken up intracellularly and released doxorubicin sequesters in the lysosome evaluated by in vitro in vivo live cell imaging
Journal of Controlled Release, 2013Co-Authors: Ann L.b. Seynhaeve, Saske Hoving, Bilyana M. Dicheva, Gerben A. Koning, Timo Ten L M HagenAbstract:Doxil, also known as Caelyx, is an established liposomal formulation of doxorubicin used for the treatment of ovarian cancer, sarcoma and multiple myeloma. While showing reduced doxorubicin related toxicity, Doxil does not greatly improve clinical outcome. To become biologically active, doxorubicin needs to be released from its carrier. Uptake and breakdown of the liposomal carrier and subsequent doxorubicin release is not fully understood and in this study we explored the hypothesis that Doxil is taken up by tumor cells and slowly degraded intracellularly. We investigated the kinetics of liposomal doxorubicin (Doxil) in vitro as well as in vivo by measuring cytotoxic effect, intracellular bioavailability and fate of the carrier and its content. To prevent fixation artifacts we applied live cell imaging in vitro and intravital microscopy in vivo. Within 8h after administration of free doxorubicin, 26% of the drug translocated to the nucleus and when reaching a specific concentration killed the cell. Unlike free doxorubicin, only 0.4% of the doxorubicin added as liposomal formulation entered the nucleus. Looking at the kinetics, we observed a build-up of nuclear doxorubicin within minutes of adding free doxorubicin. This was in contrast to Doxil showing slow translocation of doxorubicin to the nucleus and apparent accumulation in the cytoplasm. Observations made with time-lapse live cell imaging as well as in vivo intravital microscopy revealed the liposomal carrier colocalizing with doxorubicin in the cytoplasm. We also demonstrated the sequestering of liposomal doxorubicin in the lysosomal compartment resulting in limited delivery to the nucleus. This entrapment makes the bioavailable concentration of Doxil-delivered doxorubicin significantly lower and therefore ineffective as compared to free doxorubicin in killing tumor cells.
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Intact Doxil is taken up intracellularly and released doxorubicin sequesters in the lysosome: Evaluated by in vitro/in vivo live cell imaging
Journal of controlled release : official journal of the Controlled Release Society, 2013Co-Authors: Ann L.b. Seynhaeve, Saske Hoving, Bilyana M. Dicheva, Gerben A. Koning, Timo L.m. Ten HagenAbstract:Doxil, also known as Caelyx, is an established liposomal formulation of doxorubicin used for the treatment of ovarian cancer, sarcoma and multiple myeloma. While showing reduced doxorubicin related toxicity, Doxil does not greatly improve clinical outcome. To become biologically active, doxorubicin needs to be released from its carrier. Uptake and breakdown of the liposomal carrier and subsequent doxorubicin release is not fully understood and in this study we explored the hypothesis that Doxil is taken up by tumor cells and slowly degraded intracellularly. We investigated the kinetics of liposomal doxorubicin (Doxil) in vitro as well as in vivo by measuring cytotoxic effect, intracellular bioavailability and fate of the carrier and its content. To prevent fixation artifacts we applied live cell imaging in vitro and intravital microscopy in vivo. Within 8h after administration of free doxorubicin, 26% of the drug translocated to the nucleus and when reaching a specific concentration killed the cell. Unlike free doxorubicin, only 0.4% of the doxorubicin added as liposomal formulation entered the nucleus. Looking at the kinetics, we observed a build-up of nuclear doxorubicin within minutes of adding free doxorubicin. This was in contrast to Doxil showing slow translocation of doxorubicin to the nucleus and apparent accumulation in the cytoplasm. Observations made with time-lapse live cell imaging as well as in vivo intravital microscopy revealed the liposomal carrier colocalizing with doxorubicin in the cytoplasm. We also demonstrated the sequestering of liposomal doxorubicin in the lysosomal compartment resulting in limited delivery to the nucleus. This entrapment makes the bioavailable concentration of Doxil-delivered doxorubicin significantly lower and therefore ineffective as compared to free doxorubicin in killing tumor cells.
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Addition of low-dose tumor necrosis factor-α to systemic treatment with STEALTH liposomal doxorubicin (Doxil) improved anti-tumor activity in osteosarcoma-bearing rats
Anti-cancer drugs, 2005Co-Authors: Saske Hoving, Ann L.b. Seynhaeve, Sandra T. Van Tiel, Alexander M.m. Eggermont, Timo L.m. Ten HagenAbstract:Improved efficacy of Doxil (STEALTH liposomal doxorubicin) compared to free doxorubicin has been demonstrated in the treatment of several tumor types. We have shown that addition of low-dose tumor necrosis factor (TNF) to systemic Doxil administration dramatically improved tumor response in the highly vascularized rat soft tissue sarcoma BN175. Whether a similar enhanced efficacy can be achieved in less vascularized tumors is uncertain. We therefore examined the effect of systemic administration of Doxil in combination with low-dose TNF in intermediate vascularized osteosarcoma-bearing rats (ROS-1). Small fragments of the osteosarcoma were implanted s.c. in the lower limb. Treatment was started when the tumors reached an average diameter of 1 cm. Rats were treated with five i.v. injections at 4-day intervals with Doxil or doxorubicin and TNF. Systemic treatment with Doxil resulted in a better tumor growth delay than free doxorubicin, but with progressive diseases in all animals. The 3.5-fold augmented accumulation of Doxil compared to free doxorubicin presumably explains the enhanced tumor regression. Addition of low-dose TNF augmented the anti-tumor activity of Doxil, although no increased drug uptake was found compared to Doxil alone. In vitro studies showed that ROS-1 is sensitive to TNF, but systemic treatment with TNF alone did not result in a tumor growth delay. Furthermore, we demonstrated that treatment with Doxil alone or with TNF resulted in massive coagulative necrosis of tumor tissue. In conclusion, combination therapy of Doxil and low-dose TNF seems attractive for the treatment of highly vascularized tumors, but also of intermediate vascularized tumors like the osteosarcoma.
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Low‐dose tumor necrosis factor‐α augments antitumor activity of stealth liposomal doxorubicin (Doxil®) in soft tissue sarcoma‐bearing rats
International journal of cancer, 2000Co-Authors: Timo L.m. Ten Hagen, Ann L.b. Seynhaeve, Sandra T. Van Tiel, Alexander H. Van Der Veen, P.t.g.a. Nooijen, Alexander M.m. EggermontAbstract:It has previously been demonstrated in the setting of an isolated limb perfusion that application of high-dose TNF-α in combination with chemotherapy (melphalan, doxorubicin) results in strong synergistic antitumor effects in both the clinical and preclinical settings. In this study, we demonstrate that systemic administration of low-dose TNF-α augments the antitumor activity of a liposomal formulation of doxorubicin (Doxil®). Addition of TNF-α to a Doxil® regimen, which by itself induced some tumor growth delay, resulted in massive necrosis and regression of tumors. Furthermore, we could demonstrate a significant increase of liposomal drug in the tumor tissue when TNF-α had been co-administered. Administration of TNF-α augmented Doxil® accumulation only after repeated injections, whereas accumulation of free doxorubicin was not affected by TNF-α. Drug levels in the tumor interstitium appeared crucial as intracellular levels of free or liposome-associated doxorubicin were not increased by TNF-α. Therefore, we hypothesize that low-dose TNF-α augments leakage of liposomal drug into the tumor interstitium, explaining the observed improved antitumor effects. Regarding the effects of systemic administration of low doses of TNF-α, these findings may be important for enhanced tumor targeting of various liposomal drug formulations. Int. J. Cancer 87:829–837, 2000. © 2000 Wiley-Liss, Inc.
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low dose tumor necrosis factor α augments antitumor activity of stealth liposomal doxorubicin Doxil in soft tissue sarcoma bearing rats
International Journal of Cancer, 2000Co-Authors: Timo Ten L M Hagen, Ann L.b. Seynhaeve, Sandra T. Van Tiel, Alexander H. Van Der Veen, P.t.g.a. Nooijen, Alexander M.m. EggermontAbstract:It has previously been demonstrated in the setting of an isolated limb perfusion that application of high-dose TNF-α in combination with chemotherapy (melphalan, doxorubicin) results in strong synergistic antitumor effects in both the clinical and preclinical settings. In this study, we demonstrate that systemic administration of low-dose TNF-α augments the antitumor activity of a liposomal formulation of doxorubicin (Doxil®). Addition of TNF-α to a Doxil® regimen, which by itself induced some tumor growth delay, resulted in massive necrosis and regression of tumors. Furthermore, we could demonstrate a significant increase of liposomal drug in the tumor tissue when TNF-α had been co-administered. Administration of TNF-α augmented Doxil® accumulation only after repeated injections, whereas accumulation of free doxorubicin was not affected by TNF-α. Drug levels in the tumor interstitium appeared crucial as intracellular levels of free or liposome-associated doxorubicin were not increased by TNF-α. Therefore, we hypothesize that low-dose TNF-α augments leakage of liposomal drug into the tumor interstitium, explaining the observed improved antitumor effects. Regarding the effects of systemic administration of low doses of TNF-α, these findings may be important for enhanced tumor targeting of various liposomal drug formulations. Int. J. Cancer 87:829–837, 2000. © 2000 Wiley-Liss, Inc.
Mahmoud Reza Jaafari - One of the best experts on this subject based on the ideXlab platform.
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Liposomal doxorubicin targeting mitochondria: A novel formulation to enhance anti-tumor effects of Doxil® in vitro and in vivo
Journal of Drug Delivery Science and Technology, 2021Co-Authors: Saeed Mohammadian Haftcheshmeh, Mahmoud Reza Jaafari, Amin Mehrabian, Mohammad Mashreghi, Seyedeh Hoda Alavizadeh, Parvin Zamani, Javad Zarqi, Mohammad Darvishi, Fatemeh GheybiAbstract:Abstract For the treatment of many types of cancers, targeting drug delivery vehicles to the mitochondria is a major area of interest which provides a significant strategy. This study aimed to investigate whether modifying Doxil® with mitochondriotropic SS-02 peptide could improve the therapeutic efficacy of liposomal formulation in vitro and in vivo. To this purpose, the peptide conjugation was done through the covalent coupling of the cysteine thiol group of SS-02 peptide to the pyrrole group of maleimide. The novel formulations of SS-02-Doxil® (100 and 200 peptides on Doxil® surface) were prepared by post-insertion which were well characterized. In vitro study indicated that Doxil® modification with SS-02 peptides could effectively enhance the cytotoxicity, cellular binding, and uptake in TUBO tumor cells. Moreover, the increase in caspase-3, and caspase-9 activities was observed in TUBO cells following the treatment with SS-02-Doxil® formulations that confirm the mitochondria targeting. Following the administration of formulations at 10 mg/kg doxorubicin in mice model of breast cancer, SS-02-Doxil® formulations significantly reduced the growth of tumor which improved animals' survival compared to Doxil®. Furthermore, the findings of in vitro and in vivo studies indicate that Doxil® modification with SS-02 peptide could improve the therapeutic efficacy due to targeting the mitochondria of tumor cells.
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Encapsulated Checkpoint Blocker Before Chemotherapy: The Optimal Sequence of Anti-CTLA-4 and Doxil Combination Therapy.
International journal of nanomedicine, 2020Co-Authors: Reza Alimohammadi, Mahmoud Reza Jaafari, Razieh Alibeigi, Amin Reza Nikpoor, Ghanbar Mahmoodi Chalbatani, Thomas J. Webster, Seyed Amir JalaliAbstract:Introduction Today, a new paradigm has emerged for cancer treatment introducing combination therapies. Doxil, a liposomal doxorubicin serving as a chemotherapeutic agent, is an effective immunogenic killer of cancer cells. Anti-CTLA-4 has been approved for the treatment of some cancers, including melanoma, but side effects have limited its therapeutic potential. Methods In this study, two approaches were utilized to increase treatment efficiency and decrease the side effects of anti-CTLA-4, combining it with chemotherapy and encapsulation in a PEGylated liposome. A different sequence of anti-CTLA-4 and Doxil was assessed in combination therapy using non-liposomal and liposomal anti-CTLA-4. Results Our results showed that liposomal anti-CTLA-4 reduced the size of established tumors and increased survival in comparison with non-liposomal anti-CTLA-4 in a well-established B16 mouse melanoma model. In combination therapy with Doxil, only the administration of anti-CTLA-4 before Doxil showed synergism in both non-liposomal and liposomal form and increased the CD8+/regulatory T cell ratio. Discussion In summary, our results demonstrate the potential of utilizing a nanocarrier system for the delivery of checkpoint blockers, such as anti-CTLA-4 which further showed potential in a combination therapy, especially when administered before chemotherapy.
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Doxil chemotherapy plus liposomal P5 immunotherapy decreased myeloid-derived suppressor cells in murine model of breast cancer.
Nanomedicine : nanotechnology biology and medicine, 2020Co-Authors: Jamshid Gholizadeh Navashenaq, Amin Reza Nikpoor, Parvin Zamani, Jalil Tavakkol-afshari, Mahmoud Reza JaafariAbstract:Abstract Myeloid-derived suppressor cells (MDSCs) play a pivotal role in cancer. To overcome the problem of the MDSCs in the tumor microenvironment in this study, a combination of immunotherapy and chemotherapy was used. For this purpose, a liposomal formulation of P5 peptide and PEGylated liposomal doxorubicin (Doxil®) was utilized to treat mice bearing HER2+ tumor model. The results revealed that Doxil® administration before immunotherapy had not only reduced the population and functions of the MDSCs in the spleen (P
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effects of immunization against pcsk9 in an experimental model of breast cancer
Archives of Medical Science, 2019Co-Authors: Amir Abbas Momtaziborojeni, Mahmoud Reza Jaafari, Maryam Ebrahimi Nik, Maciej Banach, Amirhossein SahebkarAbstract:Introduction Inhibition of proprotein convertase subtilisin/kexin 9 (PCSK9) is an efficient strategy for lowering low-density lipoprotein cholesterol (LDL-C). There are, however, scant data on the efficacy and safety of PCSK9 inhibitors in non-cardiovascular diseases, particularly cancer. The present study aimed to evaluate the effect of PCSK9 inhibition using a nanoliposomal antiPCSK9 vaccine on cancer behavior and endpoints in mice bearing breast tumor. Material and methods To induce antiPCSK9 antibody in vivo, a nanoliposomal antiPCSK9 vaccine absorbed on 0.4% alum adjuvant was used. To induce tumor, BALB/c mice were subcutaneously inoculated with 4T1 breast carcinoma cells. After the tumor mass was palpable (approximately 10 mm3), the mice were randomly divided into four groups and subjected to different treatment protocols: (1) PBS (untreated control), (2) vaccine group, (3) combination of vaccine and Doxil, and (4) Doxil (positive control) group. Vaccine was subcutaneously administered to mice four times at 2-week intervals. Two weeks after the last administration, the vaccinated and non-vaccinated mice were subcutaneously inoculated with 4T1 breast carcinoma cells. To evaluate therapeutic efficacy, mouse body weight, tumor size, and survival were monitored every other day for 60 days. Results The nanoliposomal antiPCSK9 vaccine was found to efficiently induce specific antibodies against PCSK9 in BALB/c mice, thereby decreasing plasma levels of PCSK9 and inhibiting its function. Tumor size analysis showed that time to reach endpoint (TTE) of the vaccine, combination, Doxil, and control groups was 47 ±10, 57 ±4, 60 ±4 and 39 ±9 days, respectively. Rate of tumor growth in vaccine, combination and Doxil groups was decreased by 21%, 48% and 53%, respectively, compared to the control group. Lifespan was increased by 4.2% in the vaccine group, compared with the control group. Additionally, the survival in the combination and Doxil groups was significantly higher than the vaccine and control groups. Conclusions Our results revealed that PCSK9 inhibition may moderately improve breast cancer outcomes while having no harmful effects in tumor-bearing mice.
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Targeting the leptin receptor: To evaluate therapeutic efficacy and anti-tumor effects of Doxil, in vitro and in vivo in mice bearing C26 colon carcinoma tumor.
Colloids and surfaces. B Biointerfaces, 2018Co-Authors: Shahrzad Amiri Darban, Sara Nikoofal-sahlabadi, Nafise Amiri, Nafiseh Kiamanesh, Amin Mehrabian, Bamdad Zendehbad, Zahra Gholizadeh, Mahmoud Reza JaafariAbstract:Abstract Leptin is an appetite regulatory hormone that is secreted into the blood circulation by the adipose tissue and it functions via its over expressed receptors (Ob-R) in a wide variety of cancers. In the present study, the function of a leptin-derived peptide (LP16, 91–110 of Leptin) was investigated as a targeting ligand to decorate PEGylated liposomal doxorubicin (PLD, Doxil ® ) surface and the anti-tumor activity and therapeutic efficacy of Doxil in C26 (Colon Carcinoma) tumor model were also evaluated. As a result of this, Doxil with different LP16 peptide density (25, 50, 100 and 200 peptide on the surface of each liposome) was successfully prepared and characterized. In vitro results showed significant enhanced cytotoxicity and cellular binding and uptake of LP16-targeted Doxil formulations (LP16-Doxil) in C26 cells as compared to Doxil. In BALB/c mice bearing C26 murine carcinoma, at a dose of 15 mg/kg, LP16-Doxil groups (100 ligand) significantly suppressed the growth of the tumor and showed higher inclination to tumor as compared to non-targeted Doxil. This study revealed that the potential of LP16 peptide targeting increased the therapeutic efficacy of Doxil and highlighted the importance of optimizing the ligand density to maximize the targeting ability of the nanocarriers and merits further investigations.