- Email: [email protected]
Folic acid and peptides in targeting strategies
156
Oral Abstracts
cancers, small cancer lesions in the bladder wall were cystoscopically observed by PDD. Also, we performed PDT against this model. The selective accumulation of the micelles in the tumor tissue and homogeneous light illumination to the bladder wall allowed significant reduction of the tumor volume without any damage to normal bladder tissues. Finally, I will talk about design of nanocarriers for photochemical internalization (PCI). We succeeded in the light-selective, site-directed gene transfection and enhancement of chemotherapeutic agent against the drug-resistant tumors.
indicating that PCI may have a variety of useful applications for sitespecific drug delivery, e.g. in gene therapy, vaccination and cancer treatment. Our studies also indicate that PCI of bleomycin is superior to PDT in targeting the tumor periphery and that this is partly the cause of the improved treatment effect of PCI as compared to PDT. Recent advances in understanding the mechanisms of action as well as the development of PCI towards clinical utilization will be presented. doi:10.1016/j.pdpdt.2011.03.111
doi:10.1016/j.pdpdt.2011.03.109
O106
O104 mTHPC-based biodegradable nanoparticles for cancer treatment L. Bezdetnaya, H.P. Lassalle, J. Garrier, M.A. D’Hallewin, S. Marchal, F. Guillemin CRAN-UMR 7039, Nancy-University, Vandoeuvre-les-Nancy, France
Centre
Alexis
Vautrin,
A serious limitation of photodynamic therapy (PDT) is the absence of specific cancer targeting, resulting in an excessive tissue destruction, which can provoke life threatening situations. To partially overcome these constraints, incorporation of the active compound into liposomal nanoparticles can be proposed. Embedding of active drugs in liposomes favours passive targeting of tumors through Enhanced Permeability Retention (EPR) effect. Liposomal formulations of mTHPC (Foslip® ) enable a more selective and faster accumulation of drugs in the tumors, with a faster clearance, together with at least similar to liposomes-free mTHPC therapeutic efficacy. Best Foslip® — photoinduced response was obtained from the study of spatial intratumoral Foslip distribution rather than from bulk pharmacological tissues pharmacokinetics. Comprehension of the transport kinetics of the photosensitizer from the vessels towards extravascular structures is essential for optimizing clinical protocols. We have observed different redistribution patterns of mTHPC to plasma components according to liposomal composition (conventional vs. pegylated liposomes) in vitro. The visualization of these processes in real time in vivo using the chick chorio allantoic membrane (CAM) model corroborate with in vivo results. Future directions consist in aptamer-mediated targeted delivery of chlorin types photosensitizers to tumor tissues.
Novel optical probes for image-guided tumor resection and photodynamic therapy based on glucose transporters E. Moriyama, W. Cao, T. Liu, H. Wang, G. Zheng, B. Wilson Ontario Cancer Institute, Division of Biophysics and Bioimaging, Canada Tumors often present a shift in glucose metabolism towards a less energy-efficient glycolytic mechanism. This characteristic has been employed for metabolic imaging of primary and metastatic tumors using the contrast agent Fluorodeoxy-D-Glucose for Positron Emission Tomography (FDG-PET). We propose to synthesize optical analogues of FDG-PET agents based on aminolevulinic acid (ALA2DG) as a novel agent for Fluorescence Guided Tumor Resection (FGR) and photodynamic therapy (PDT). The ultimate goal is to exploit the increased expression of glucose transporters (GLUTs) present in many solid tumors in order to improve the efficacy of these two clinical techniques. We have successfully developed the first ALA-2DG conjugate designed for Fluorescence Guided Resection (FGR) and PDT of brain tumors. The initial results demonstrate the ALA-2DG uptake by glucose transporters followed by intracellular PpIX production. These promising results open new possibilities for combined multi-modality tumor imaging/therapeutics through the development of new agents for targeted FGR and PDT based on tumor metabolism. This project is funded by the American Society for Lasers in Medicine and Surgery (ASLMS). The authors would like to thank Lili Ding for technical support. doi:10.1016/j.pdpdt.2011.03.112
doi:10.1016/j.pdpdt.2011.03.110 O105 Photochemical internalization (PCI), a technology for sitespecific drug delivery. Recent advances Kristian Berg, Anette Weyergang, Marie Vikdal, Ole-Jacob Norum, Maria Berstad, PÖL Selbo
O107 Folic acid and peptides in targeting strategies M. Barberi-Heyob 1 , C. Frochot 2 , R. Vanderesse 3 , T. Bastogne 4 , F. Guillemin 1 1
The Norwegian Radium Hospital, Department of Radiation Biology, Oslo, Norway
CRAN, CNRS, Nancy-University, CAV, Vandoeuvre-les-nancy, France LRGP, CNRS, Nancy, France 3 LCPM, CNRS, Nancy-University, Nancy, France 4 CRAN, CNRS, Nancy-University, Vandoeuvre-les-nancy, France
Photochemical internalisation (PCI) is a novel technology for release of endocytosed macromolecules into the cytosol. The technology is based on the use of photosensitizers located in endocytic vesicles that upon activation by light induces a release of macromolecules from their compartmentalization in endocytic vesicles. PCI has been shown to enhance the biological activity of a large variety of macromolecules and other molecules that do not readily penetrate the plasma membrane, including type I ribosomeinactivating proteins (RIPs), gene-encoding plasmids, adenovirus, oligonucleotides and the chemotherapeuticum bleomycin. PCI has also been shown to enhance the treatment effect of targeted therapeutic macromolecules. The results show that PCI can induce efficient light-directed delivery of macromolecules into the cytosol,
Introduction: The ability to confine activation of the photosensitizer by restricting illumination to the tumor allows for a certain degree of selectivity. Nevertheless, the targeted delivery of photosensitizers to defined cells is a challenge in PDT of cancer, and one area of importance is photosensitizer targeting. Numerous interesting works have clearly demonstrated that more specific drug targeting and cellular uptake can be achieved by binding various ligands, known as targeting moieties, such as peptides, growth factors, antibodies or antibody fragments, oligonucleotide aptamers and small compounds such as folate that can recognize tumor cell markers. Method: The rational of all these strategies is taken from biologic and molecular characteristics of tumor tissues. Presentation
2
Oral Abstracts
157
will be focused on the recent and significant published articles of our group using folic acid or peptide moiety in targeting strategies in PDT and also in vascular-targeted PDT. Results: We will illustrate the in vivo selectivity of m-THPC-like photosensitizer conjugated to folic acid (Bioog Med Chem, 2006; J Med Chem, 2008). Tumor neovasculature targeting also appears as an approach of significant research interest for the development of active photosensitizer-delivery technologies able to enhance selectivity and efficiency of vascular PDT for cancer treatment. Conclusion: Targeting neuropilin-1 can lead to the selective vascular localization of photosensitizers, and thus enhance the vascular photodynamic effects (J Control Release, 2006; Drug Metabol Disp, 2007; Photochem Photobiol Sci, 2008; Int J Radiat Oncol Biol Phys, 2009; Pharm Res, 2010; Biochem Pharmacol, 2010). doi:10.1016/j.pdpdt.2011.03.113 O108 Cellulose nanocrystals: A new chlorin carrier designed for photodynamic therapy: Synthesis, characterization and potent anti-tumoural activity N. Drogat 1 , R. Granet 1 , V. Sol 1 , C. Le Morvan 1 , G. BegaudGrimaud 1 , F. Lallouet 2 , P. Krausz 1 1
Universite de Limoges, Laboratoire de Chimie des Substances Naturelles, EA 1069, France 2 Universite de Limoges, Homeostasie Cellulaire et Pathologies, EA 3842, France Nanoparticle carriers represent a great breakthrough for drug targeting and delivery and stand at the forefront of nanomedicine research. Solid tumours with their neo-vascularisation, characterized by slacked junctions between endothelial cells suffer from leaky vasculature and poor lymphatic drainage. These characteristics could allow the passive accumulation of nanoparticles in the range of 50—200 nm, named enhanced permeability and retention (EPR) effect. To reach the targeted tumoural tissue, nanoparticles must be able to stay intact in the bloodstream for sufficient time lapses. According to the literature, for a prolonged blood circulation time, carriers have to be small, constituted of natural compounds and must present a neutral and hydrophilic surface. Cellulose nanocrystals (CNCs) were imagined based on these requirements of size and hydrophilicity were chosen as carriers. To evaluate their potential, CNCs were labeled by ionic and covalent ways with polyaminated chlorin p6.
These susceptible biocompatible photosensitizers (PS), stable in water, were tested in vitro for their photoactivable antitumour activity. Assays pursued on human keratinocyte HaCat cell line revealed IC50 values within the nanomolar-range, making these cellulose nanocrystal-based photosensitizers promising candidates for in vivo investigations. doi:10.1016/j.pdpdt.2011.03.114 O109 Why use nanoparticles as photosensitizers for PDT? R. Kopelman 1 , Y.E.K. Lee 1 , S. Wang 1 , H.J. Hah 1 , G. Kim 1 , M. Nie 1 , M. Qin 1 , O. Sagher 2 , D. Orringer 2 , M. Philbert 3 , K. Herrmann 1 , R. Pandey 4 1
University of Michigan, Chemistry, Ann Arbor, United States University of Michigan, Neurosurgery, Ann Arbor, United States 3 University of Michigan, School of Public Health, Ann Arbor, United States 4 Roswell Park Cancer Institute, PDT Center, Buffalo, NY, United States 2
Some of the advantages in using nanoparticles as PDT agents are: 1. Selective targeting of tumor cells and even subcellular domains. 2. Hi critical mass of photosensitizers. 3. Resistance to MDR. 4. Multifunctionality (e.g. combined with enhanced contrast MRI or fluorescence imaging). 5. Protection of photosensitizer molecules. 6. Engineerability (e.g. size, matrix, chemical and physical loading, philicity, delivery rate, biodegradation). 7. Enhanced stability. An example matrix is polyacrylamide (a typical hydrogel), which exhibits sufficient porosity to singlet oxygen, good protection from plasma enzymes, minimal toxicity, sufficient bio-elimination in size-range of 30—100 nm, excellent engineerability and stability.
Oral Abstracts
cancers, small cancer lesions in the bladder wall were cystoscopically observed by PDD. Also, we performed PDT against this model. The selective accumulation of the micelles in the tumor tissue and homogeneous light illumination to the bladder wall allowed significant reduction of the tumor volume without any damage to normal bladder tissues. Finally, I will talk about design of nanocarriers for photochemical internalization (PCI). We succeeded in the light-selective, site-directed gene transfection and enhancement of chemotherapeutic agent against the drug-resistant tumors.
indicating that PCI may have a variety of useful applications for sitespecific drug delivery, e.g. in gene therapy, vaccination and cancer treatment. Our studies also indicate that PCI of bleomycin is superior to PDT in targeting the tumor periphery and that this is partly the cause of the improved treatment effect of PCI as compared to PDT. Recent advances in understanding the mechanisms of action as well as the development of PCI towards clinical utilization will be presented. doi:10.1016/j.pdpdt.2011.03.111
doi:10.1016/j.pdpdt.2011.03.109
O106
O104 mTHPC-based biodegradable nanoparticles for cancer treatment L. Bezdetnaya, H.P. Lassalle, J. Garrier, M.A. D’Hallewin, S. Marchal, F. Guillemin CRAN-UMR 7039, Nancy-University, Vandoeuvre-les-Nancy, France
Centre
Alexis
Vautrin,
A serious limitation of photodynamic therapy (PDT) is the absence of specific cancer targeting, resulting in an excessive tissue destruction, which can provoke life threatening situations. To partially overcome these constraints, incorporation of the active compound into liposomal nanoparticles can be proposed. Embedding of active drugs in liposomes favours passive targeting of tumors through Enhanced Permeability Retention (EPR) effect. Liposomal formulations of mTHPC (Foslip® ) enable a more selective and faster accumulation of drugs in the tumors, with a faster clearance, together with at least similar to liposomes-free mTHPC therapeutic efficacy. Best Foslip® — photoinduced response was obtained from the study of spatial intratumoral Foslip distribution rather than from bulk pharmacological tissues pharmacokinetics. Comprehension of the transport kinetics of the photosensitizer from the vessels towards extravascular structures is essential for optimizing clinical protocols. We have observed different redistribution patterns of mTHPC to plasma components according to liposomal composition (conventional vs. pegylated liposomes) in vitro. The visualization of these processes in real time in vivo using the chick chorio allantoic membrane (CAM) model corroborate with in vivo results. Future directions consist in aptamer-mediated targeted delivery of chlorin types photosensitizers to tumor tissues.
Novel optical probes for image-guided tumor resection and photodynamic therapy based on glucose transporters E. Moriyama, W. Cao, T. Liu, H. Wang, G. Zheng, B. Wilson Ontario Cancer Institute, Division of Biophysics and Bioimaging, Canada Tumors often present a shift in glucose metabolism towards a less energy-efficient glycolytic mechanism. This characteristic has been employed for metabolic imaging of primary and metastatic tumors using the contrast agent Fluorodeoxy-D-Glucose for Positron Emission Tomography (FDG-PET). We propose to synthesize optical analogues of FDG-PET agents based on aminolevulinic acid (ALA2DG) as a novel agent for Fluorescence Guided Tumor Resection (FGR) and photodynamic therapy (PDT). The ultimate goal is to exploit the increased expression of glucose transporters (GLUTs) present in many solid tumors in order to improve the efficacy of these two clinical techniques. We have successfully developed the first ALA-2DG conjugate designed for Fluorescence Guided Resection (FGR) and PDT of brain tumors. The initial results demonstrate the ALA-2DG uptake by glucose transporters followed by intracellular PpIX production. These promising results open new possibilities for combined multi-modality tumor imaging/therapeutics through the development of new agents for targeted FGR and PDT based on tumor metabolism. This project is funded by the American Society for Lasers in Medicine and Surgery (ASLMS). The authors would like to thank Lili Ding for technical support. doi:10.1016/j.pdpdt.2011.03.112
doi:10.1016/j.pdpdt.2011.03.110 O105 Photochemical internalization (PCI), a technology for sitespecific drug delivery. Recent advances Kristian Berg, Anette Weyergang, Marie Vikdal, Ole-Jacob Norum, Maria Berstad, PÖL Selbo
O107 Folic acid and peptides in targeting strategies M. Barberi-Heyob 1 , C. Frochot 2 , R. Vanderesse 3 , T. Bastogne 4 , F. Guillemin 1 1
The Norwegian Radium Hospital, Department of Radiation Biology, Oslo, Norway
CRAN, CNRS, Nancy-University, CAV, Vandoeuvre-les-nancy, France LRGP, CNRS, Nancy, France 3 LCPM, CNRS, Nancy-University, Nancy, France 4 CRAN, CNRS, Nancy-University, Vandoeuvre-les-nancy, France
Photochemical internalisation (PCI) is a novel technology for release of endocytosed macromolecules into the cytosol. The technology is based on the use of photosensitizers located in endocytic vesicles that upon activation by light induces a release of macromolecules from their compartmentalization in endocytic vesicles. PCI has been shown to enhance the biological activity of a large variety of macromolecules and other molecules that do not readily penetrate the plasma membrane, including type I ribosomeinactivating proteins (RIPs), gene-encoding plasmids, adenovirus, oligonucleotides and the chemotherapeuticum bleomycin. PCI has also been shown to enhance the treatment effect of targeted therapeutic macromolecules. The results show that PCI can induce efficient light-directed delivery of macromolecules into the cytosol,
Introduction: The ability to confine activation of the photosensitizer by restricting illumination to the tumor allows for a certain degree of selectivity. Nevertheless, the targeted delivery of photosensitizers to defined cells is a challenge in PDT of cancer, and one area of importance is photosensitizer targeting. Numerous interesting works have clearly demonstrated that more specific drug targeting and cellular uptake can be achieved by binding various ligands, known as targeting moieties, such as peptides, growth factors, antibodies or antibody fragments, oligonucleotide aptamers and small compounds such as folate that can recognize tumor cell markers. Method: The rational of all these strategies is taken from biologic and molecular characteristics of tumor tissues. Presentation
2
Oral Abstracts
157
will be focused on the recent and significant published articles of our group using folic acid or peptide moiety in targeting strategies in PDT and also in vascular-targeted PDT. Results: We will illustrate the in vivo selectivity of m-THPC-like photosensitizer conjugated to folic acid (Bioog Med Chem, 2006; J Med Chem, 2008). Tumor neovasculature targeting also appears as an approach of significant research interest for the development of active photosensitizer-delivery technologies able to enhance selectivity and efficiency of vascular PDT for cancer treatment. Conclusion: Targeting neuropilin-1 can lead to the selective vascular localization of photosensitizers, and thus enhance the vascular photodynamic effects (J Control Release, 2006; Drug Metabol Disp, 2007; Photochem Photobiol Sci, 2008; Int J Radiat Oncol Biol Phys, 2009; Pharm Res, 2010; Biochem Pharmacol, 2010). doi:10.1016/j.pdpdt.2011.03.113 O108 Cellulose nanocrystals: A new chlorin carrier designed for photodynamic therapy: Synthesis, characterization and potent anti-tumoural activity N. Drogat 1 , R. Granet 1 , V. Sol 1 , C. Le Morvan 1 , G. BegaudGrimaud 1 , F. Lallouet 2 , P. Krausz 1 1
Universite de Limoges, Laboratoire de Chimie des Substances Naturelles, EA 1069, France 2 Universite de Limoges, Homeostasie Cellulaire et Pathologies, EA 3842, France Nanoparticle carriers represent a great breakthrough for drug targeting and delivery and stand at the forefront of nanomedicine research. Solid tumours with their neo-vascularisation, characterized by slacked junctions between endothelial cells suffer from leaky vasculature and poor lymphatic drainage. These characteristics could allow the passive accumulation of nanoparticles in the range of 50—200 nm, named enhanced permeability and retention (EPR) effect. To reach the targeted tumoural tissue, nanoparticles must be able to stay intact in the bloodstream for sufficient time lapses. According to the literature, for a prolonged blood circulation time, carriers have to be small, constituted of natural compounds and must present a neutral and hydrophilic surface. Cellulose nanocrystals (CNCs) were imagined based on these requirements of size and hydrophilicity were chosen as carriers. To evaluate their potential, CNCs were labeled by ionic and covalent ways with polyaminated chlorin p6.
These susceptible biocompatible photosensitizers (PS), stable in water, were tested in vitro for their photoactivable antitumour activity. Assays pursued on human keratinocyte HaCat cell line revealed IC50 values within the nanomolar-range, making these cellulose nanocrystal-based photosensitizers promising candidates for in vivo investigations. doi:10.1016/j.pdpdt.2011.03.114 O109 Why use nanoparticles as photosensitizers for PDT? R. Kopelman 1 , Y.E.K. Lee 1 , S. Wang 1 , H.J. Hah 1 , G. Kim 1 , M. Nie 1 , M. Qin 1 , O. Sagher 2 , D. Orringer 2 , M. Philbert 3 , K. Herrmann 1 , R. Pandey 4 1
University of Michigan, Chemistry, Ann Arbor, United States University of Michigan, Neurosurgery, Ann Arbor, United States 3 University of Michigan, School of Public Health, Ann Arbor, United States 4 Roswell Park Cancer Institute, PDT Center, Buffalo, NY, United States 2
Some of the advantages in using nanoparticles as PDT agents are: 1. Selective targeting of tumor cells and even subcellular domains. 2. Hi critical mass of photosensitizers. 3. Resistance to MDR. 4. Multifunctionality (e.g. combined with enhanced contrast MRI or fluorescence imaging). 5. Protection of photosensitizer molecules. 6. Engineerability (e.g. size, matrix, chemical and physical loading, philicity, delivery rate, biodegradation). 7. Enhanced stability. An example matrix is polyacrylamide (a typical hydrogel), which exhibits sufficient porosity to singlet oxygen, good protection from plasma enzymes, minimal toxicity, sufficient bio-elimination in size-range of 30—100 nm, excellent engineerability and stability.