charles lollo | UC SAN DIEGO (original) (raw)
Papers by charles lollo
Journal of Chromatography B-analytical Technologies in The Biomedical and Life Sciences, 2011
CAT ((+)-(13aS)-deoxytylophorinine) is a novel anticancer drug belonging to phenanthroindolizidin... more CAT ((+)-(13aS)-deoxytylophorinine) is a novel anticancer drug belonging to phenanthroindolizidine alkaloids. A sensitive and reliable liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for simultaneous quantification of CAT and its pharmacologically active 3-O-desmethyl metabolite (S-4) was developed and validated in rat plasma using rotundine as the internal standard (IS). CAT, S-4 and IS were extracted by acetonitrile protein precipitation and separated on an Eclipse XDB-C18 column (1.8μm, 4.6mm×50mm) with acetonitrile-water (27:73, v/v) mobile phase containing 0.1% formic acid at a 0.4mL/min flow rate. Positive ion electrospray ionization in multiple reaction monitoring mode was employed to measure CAT, S-4 and IS by monitoring the transitions m/z 364.2→70.1 for CAT, 350.1→70.1 for S-4 and 356.2→192.2 for IS. Good linear correlation (r(2)>0.991) was achieved for CAT and S-4 over the range of 0.214-128.16 and 0.044-11.00ng/mL, respectively. The lower limit of quantification was 0.214ng/mL for CAT and 0.044ng/mL for S-4, using 50μL rat plasma samples. The intra- and inter-day precisions were not exceed 15% and the accuracy ranged between 94.80% and 108.22%. The average extraction recoveries of both analytes were greater than 94.62%. The method was successfully applied to the pharmacokinetic study of CAT and S-4 in rats after oral administration.
Journal of The American Chemical Society, 1984
Page 1. J. Am. Chem. Soc. 1984, 106, 2149-2753 2149 NMR Site-to-Site Rate Constants and the Mecha... more Page 1. J. Am. Chem. Soc. 1984, 106, 2149-2753 2149 NMR Site-to-Site Rate Constants and the Mechanisms of Acid-Catalyzed Proton Exchange in Secondary Amides Charles L. Perrin,* Charles Peter Lollo, and Eric R. Johnston ...
Journal of The American Chemical Society, 1984
ABSTRACT Site-to-site rate constants have been measured for acid-catalyzed proton exchange of N-m... more ABSTRACT Site-to-site rate constants have been measured for acid-catalyzed proton exchange of N-methylformamide and four primary amides in a series of solvents of varying polarity. The method involves NMR saturation-transfer measurements, sometimes combined with line-shape analysis. According to the ratio k//Z//E/k//Z//S, the mix of exchange mechanisms in primary amides does not change significantly with a moderate decrease in solvent polarity. For secondary amides there is a substantial changeover from the N-protonation mechanism to the imidic acid mechanism. This changeover is also seen for acetamide when the solvent is changed to 90% aqueous tetrahydrofuran. The solvent effect on mechanism is rationalized in terms of pKs of model compounds. The implications of these results for proton exchange in proteins are discussed. In particular, it is concluded that the NH protons of peptide backbones, both solvent exposed and buried, exchange greater than 99% via the imidic acid. The accessibility requirements of the imidic acid mechanism then support the local-unfolding model for exchange of buried protons.
Journal of Organic Chemistry, 1985
Soluble imidate anions, especially formimidate anions, HC(0-)=NR, can be prepared by treating the... more Soluble imidate anions, especially formimidate anions, HC(0-)=NR, can be prepared by treating the amide with NaH or KH in THF or Me2S0. N-Phenylformimidate anion can also be prepared in hydroxylic solvents by treating the amide with excess NaOH. The imidate anions have been characterized by proton NMR. The E stereoisomer is generally more stable than the 2, but the E/Z equilibrium constant is strongly solvent dependent.
Biochimica Et Biophysica Acta-gene Structure and Expression, 1999
We are developing a self-assembling non-viral in vivo gene delivery vehicle based on poly-L-lysin... more We are developing a self-assembling non-viral in vivo gene delivery vehicle based on poly-L-lysine and plasmid DNA. We have characterized poly-L-lysines of different chain lengths for DNA condensation and strength of DNA binding. Poly-Llysine chains s 20 residues bound DNA efficiently in physiological saline, while shorter chains did not. Attachment of asialoorosomucoid to PLL increased the PLL chain length required for efficient DNA binding in saline and for efficient DNA condensation. By electron microscopy, poly-L-lysine/DNA polyplexes appeared as toroids 25^50 nm in diameter or rods 40^80 nm long; conjugation of asialoorosomucoid to the polylysine component increased the size of resulting polyplexes to 50^90 nm. In water, poly-L-lysine and asialoorosomucoid^PLL polyplexes have effective diameters of 46 and 87.6 nm, respectively. Polyplexes containing only poly-L-lysine and DNA aggregated in physiological saline at all charge ratios and aggregated at neutral charge ratios in water. Attachment of asialoorosomucoid lessened, but did not eliminate, the aggregation of PLL polyplexes, and did not result in efficient delivery of polyplexes to hepatocytes. Conjugation of polyethylene glycol to poly-L-lysine sterically stabilized resulting polyplexes at neutral charge ratios by shielding the surfaces. For efficient in vivo gene delivery, polyplexes will need to be sterically stabilized to prevent aggregation and interaction with serum components. ß 0167-4781 / 99 / $^see front matter ß 1999 Published by Elsevier Science B.V. All rights reserved. PII: S 0 1 6 7 -4 7 8 1 ( 9 8 ) 0 0 2 7 4 -
Journal of The American Chemical Society, 1981
Page 1. J. Am. Chem. SOC. 1981, 103, 4691-4696 469 1 NMR Studies of Base-Catalyzed Proton Exchang... more Page 1. J. Am. Chem. SOC. 1981, 103, 4691-4696 469 1 NMR Studies of Base-Catalyzed Proton Exchange in Amides Charles L. Perrin,* Eric R. Johnston, Charles Peter Lollo, and Paul A. Kobrin Contribution from the Department ...
Journal of Labelled Compounds & Radiopharmaceuticals, 1978
2-Methylpropionic, n-butyric, 2-methylbutyric and n-heptanoic acids labelled with 13C or 2H at va... more 2-Methylpropionic, n-butyric, 2-methylbutyric and n-heptanoic acids labelled with 13C or 2H at various positions were synthesized. Carbon-13 was introduced to the carboxyl group by Grignard synthesis. Malonate ester synthesis was utilized to introduce labelled methyl group(s) at 2-position of the branched acids. Procedures for small scale synthesis by these commonly used methods are described in detail. In addition, a novel method for the introduction of a deuterium at the 2-position of these car-boxylic acids by decarboxylation of the corresponding carboxyl-deuterated malonic acid is described.
Expert Opinion on Biological Therapy, 2001
Chronic viral hepatitis is a major clinical problem, with over half a billion persons infected wo... more Chronic viral hepatitis is a major clinical problem, with over half a billion persons infected worldwide. Current therapies, principally treatment with recombinant IFN-alpha protein, have limited benefit. Recent studies suggest that gene-based expression of IFN-alpha is a possible therapeutic alternative that may improve the effectiveness of treatment. Gene delivery to the liver and consequent IFN-alpha expression therein, has the potential to concentrate the protein at the target organ and provide more continuous exposure to the therapeutic agent. Other potential gene and nucleic acid therapeutics for viral hepatitis are also being investigated. Key to the deployment of these future therapies is a suitable method of gene delivery. Although recombinant viral vector systems, such as adenovirus, are currently the most effective means of gene delivery to the liver, their use presents many concerns. These include immune and inflammatory reactions to the viral vector and possible adverse interactions between the recombinant virus and the pre-existing viral infection. Non-viral gene delivery systems would be a preferred treatment modality. The efficiency of current non-viral systems is not adequate for systemically administered liver gene therapy. However, recent use of membrane permeabilisation techniques has shown that high efficiency non-viral gene transfer agents are possible. The future coupling of these improved delivery systems with gene- or nucleic acid-based therapeutics currently in development holds out great promise for new generations of antihepatitis therapies.
Nucleic Acids Research, 1998
The atomic force microscope (AFM) was used to assay the extent of DNA condensation in ∼100 differ... more The atomic force microscope (AFM) was used to assay the extent of DNA condensation in ∼100 different complexes of DNA with polylysine (PL) or PL covalently attached to the glycoproteins asialoorosomucoid (AsOR) or orosomucoid (OR). The best condensation of DNA was obtained with 10 kDa PL covalently attached to AsOR, at a lysine:nucleotide (Lys:nt) ratio of 5:1 or higher. These conditions produce large numbers of toroids and short rods with contour lengths of 300-400 nm. Some DNA condensation into shortened thickened structures was seen with 10 kDa PL attached to AsOR at Lys:nt ratios of 1.6:1 and 3:1. Some DNA condensation was also seen with 4 kDa PL at Lys:nt ratios of 3:1 and higher. Little DNA condensation was seen with PL alone or with PL convalently attached to OR at Lys:nt ratios up to 6:1. AsOR-PL enhanced gene expression in the mouse liver ∼10to 50-fold as compared with PL alone.
Radiation Research, 1995
High-dose radiation therapy for liver metastases of gastrointestinal malignancies might be improv... more High-dose radiation therapy for liver metastases of gastrointestinal malignancies might be improved by combining external-beam irradiation and radioimmunoglobulin therapy. We studied the liver toxicity of the proposed combination in healthy beagle dogs. A total dose of 30 Gy to the whole liver, delivered in 2-Gy fractions over 3 weeks, resulted in mild, temporary veno-occlusive disease (VOD) in three of three dogs. Reversible bone marrow damage was noted after two intravenous injections of 18.5 MBq of yttrium-90-labeled monoclonal antibody ZCE025 per kg body weight in three of three dogs. Administrations of the antibody were separated by 1 week. Three dogs treated by irradiation of the liver with radioimmunoglobulin therapy added during the last 2 weeks of the irradiation showed signs of radiation hepatitis (VOD) starting around 35 days after treatment. One dog had a complete recovery, and two dogs were euthanized in a stage of terminal liver failure around day 90 after treatment. Temporary bone marrow damage was observed after the combined treatment, similar to the bone marrow damage observed after radioimmunoglobulin therapy alone. Earlier studies in the same dog model showed that bone marrow is the dose-limiting organ if radioimmunoglobulin therapy is used alone. The addition of irradiation of the liver to radioimmunoglobulin therapy changes the dose-limiting organ from bone marrow to liver. The radiation hepatitis observed in dogs is very similar to that observed in humans and is reflected in early platelet consumption in the irradiated liver plus late elevations of liver enzymes and VOD in central hepatic veins on histological analysis. Future applications of combined liver irradiation and radioimmunoglobulin therapy in humans should use radioimmunoglobulin therapy agents which show minimal uptake by normal liver.
Biochimica Et Biophysica Acta-general Subjects, 2000
In vitro assays have demonstrated the capability of poly-L-lysine to protect plasmid DNA from ser... more In vitro assays have demonstrated the capability of poly-L-lysine to protect plasmid DNA from serum nucleases and cellular lysates. Our purpose was to evaluate the stability and potency of poly-L-lysine^DNA polyplexes after intravenous injection into mice. Polyplexes consisted of 32 P-radiolabeled plasmid DNA complexed with poly-L-lysine at specified charge ratios. Variations in conjugate hydrophobicity and levels of modification with polyethylene glycol were investigated. Our results show that, in contrast to in vitro studies, the systemically administered polyplexes exhibited marked DNA degradation in the vascular compartment within 5 min. Substitution of poly-L-lysine O-amino sites with polyethylene glycol or hydrocarbon chains resulted in faster degradation even when complexed at higher charge ( þ ) ratios. Use of excess cationic charge in the polyplexes ( þ 2.5) diminished degradation rates only slightly. An analysis was made of the strength of the poly-L-lysine:DNA interaction by competition with poly-aspartic acid. Polyplexes with the strongest binding between conjugate and DNA in the competition assay were also the most stable in blood. However, tighter binding was not enough to fully protect the polyplex in vivo and polyplex DNA was substantially degraded within 10 min. Increased polyplex stability did not correlate with improved in vivo transfection efficiency. ß
Nuclear Medicine Communications, 1994
High background activity produces imaging problems when scanning with antibodies. The following w... more High background activity produces imaging problems when scanning with antibodies. The following work is directed towards reducing this background. The murine monoclonal antibody (MAb) CHA-255 selectively binds 111In-nitrobenzyl EDTA, a molecule referred to as a 'hapten'. Balb/c mice studies indicate that if the antibody is administered prior to the hapten, it predictably modifies the biodistribution and pharmacokinetics of the hapten. The pharmacokinetics for the hapten were proportional to antibody dose and inversely proportional to the time interval between injection of the antibody and the hapten. A hybrid MAb was produced by the enzymatic digestion of CHA-255 and ZCE-025, an anticarcinoembryonic antigen (CEA) MAb, followed by joining of the two via a thioether linkage. The result was a F(ab')2 with affinity for both CEA and the hapten. The pharmacokinetics of the hapten were again dependent upon the kinetics and distribution of the hybrid antibody. Data in tumour models are also presented for 111In-nitrobenzyl EDTA and 111In-thioureabenzyl EDTA (TUBE), a newer hapten. The data indicate that the antibody-hapten system is capable of targeting tumour quickly while normal tissue rapidly becomes depleted of radioactivity. We conclude that the hapten-antibody technique shows some advantages over directly labelled MAb as a targeting system.
International Journal of Radiation Oncology Biology Physics, 1986
A new radiolabel 90Yttrium has been chelated to antiferritin antibodies for the treatment of hepa... more A new radiolabel 90Yttrium has been chelated to antiferritin antibodies for the treatment of hepatocellular cancer. The isotope 90Yttrium has the advantage of no significant external radiation to other individuals, that is, outpatient therapy and potentially more therapeutic power with an increase from 0.3 Mev 131I beta radiation to 0.9 Mev 90Yttrium pure beta radiation. Six patients treated in the Phase I study have had modest hematologic toxicity and two have had partial remissions of their primary tumors. One of these patients has had complete remission of a pulmonary metastasis. The use of external radiation (900 rad) to the primary tumor in advance of radiolabeled antibody administration has increased antibody uptake and increased tumor dose rate and total dose. An extensive study of 90Yttrium antiferritin is planned.
Journal of Macromolecular Science, Part A, 1999
... MARIUSZ G. BANASZCZYK,* CHARLES P. LOLLO, DEBORAH Y. KWOH, ALISON T. PHILLIPS, ARJANG AMINI, ... more ... MARIUSZ G. BANASZCZYK,* CHARLES P. LOLLO, DEBORAH Y. KWOH, ALISON T. PHILLIPS, ARJANG AMINI, DUNCAN P. WU, PATRICIA M. MULLEN ... washed 2x by placing on a distilled water droplet for 15 seconds followed by thoroughly removingliquid by wicking to filter. ...
Journal of Chromatography B-analytical Technologies in The Biomedical and Life Sciences, 2011
CAT ((+)-(13aS)-deoxytylophorinine) is a novel anticancer drug belonging to phenanthroindolizidin... more CAT ((+)-(13aS)-deoxytylophorinine) is a novel anticancer drug belonging to phenanthroindolizidine alkaloids. A sensitive and reliable liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for simultaneous quantification of CAT and its pharmacologically active 3-O-desmethyl metabolite (S-4) was developed and validated in rat plasma using rotundine as the internal standard (IS). CAT, S-4 and IS were extracted by acetonitrile protein precipitation and separated on an Eclipse XDB-C18 column (1.8μm, 4.6mm×50mm) with acetonitrile-water (27:73, v/v) mobile phase containing 0.1% formic acid at a 0.4mL/min flow rate. Positive ion electrospray ionization in multiple reaction monitoring mode was employed to measure CAT, S-4 and IS by monitoring the transitions m/z 364.2→70.1 for CAT, 350.1→70.1 for S-4 and 356.2→192.2 for IS. Good linear correlation (r(2)>0.991) was achieved for CAT and S-4 over the range of 0.214-128.16 and 0.044-11.00ng/mL, respectively. The lower limit of quantification was 0.214ng/mL for CAT and 0.044ng/mL for S-4, using 50μL rat plasma samples. The intra- and inter-day precisions were not exceed 15% and the accuracy ranged between 94.80% and 108.22%. The average extraction recoveries of both analytes were greater than 94.62%. The method was successfully applied to the pharmacokinetic study of CAT and S-4 in rats after oral administration.
Journal of The American Chemical Society, 1984
Page 1. J. Am. Chem. Soc. 1984, 106, 2149-2753 2149 NMR Site-to-Site Rate Constants and the Mecha... more Page 1. J. Am. Chem. Soc. 1984, 106, 2149-2753 2149 NMR Site-to-Site Rate Constants and the Mechanisms of Acid-Catalyzed Proton Exchange in Secondary Amides Charles L. Perrin,* Charles Peter Lollo, and Eric R. Johnston ...
Journal of The American Chemical Society, 1984
ABSTRACT Site-to-site rate constants have been measured for acid-catalyzed proton exchange of N-m... more ABSTRACT Site-to-site rate constants have been measured for acid-catalyzed proton exchange of N-methylformamide and four primary amides in a series of solvents of varying polarity. The method involves NMR saturation-transfer measurements, sometimes combined with line-shape analysis. According to the ratio k//Z//E/k//Z//S, the mix of exchange mechanisms in primary amides does not change significantly with a moderate decrease in solvent polarity. For secondary amides there is a substantial changeover from the N-protonation mechanism to the imidic acid mechanism. This changeover is also seen for acetamide when the solvent is changed to 90% aqueous tetrahydrofuran. The solvent effect on mechanism is rationalized in terms of pKs of model compounds. The implications of these results for proton exchange in proteins are discussed. In particular, it is concluded that the NH protons of peptide backbones, both solvent exposed and buried, exchange greater than 99% via the imidic acid. The accessibility requirements of the imidic acid mechanism then support the local-unfolding model for exchange of buried protons.
Journal of Organic Chemistry, 1985
Soluble imidate anions, especially formimidate anions, HC(0-)=NR, can be prepared by treating the... more Soluble imidate anions, especially formimidate anions, HC(0-)=NR, can be prepared by treating the amide with NaH or KH in THF or Me2S0. N-Phenylformimidate anion can also be prepared in hydroxylic solvents by treating the amide with excess NaOH. The imidate anions have been characterized by proton NMR. The E stereoisomer is generally more stable than the 2, but the E/Z equilibrium constant is strongly solvent dependent.
Biochimica Et Biophysica Acta-gene Structure and Expression, 1999
We are developing a self-assembling non-viral in vivo gene delivery vehicle based on poly-L-lysin... more We are developing a self-assembling non-viral in vivo gene delivery vehicle based on poly-L-lysine and plasmid DNA. We have characterized poly-L-lysines of different chain lengths for DNA condensation and strength of DNA binding. Poly-Llysine chains s 20 residues bound DNA efficiently in physiological saline, while shorter chains did not. Attachment of asialoorosomucoid to PLL increased the PLL chain length required for efficient DNA binding in saline and for efficient DNA condensation. By electron microscopy, poly-L-lysine/DNA polyplexes appeared as toroids 25^50 nm in diameter or rods 40^80 nm long; conjugation of asialoorosomucoid to the polylysine component increased the size of resulting polyplexes to 50^90 nm. In water, poly-L-lysine and asialoorosomucoid^PLL polyplexes have effective diameters of 46 and 87.6 nm, respectively. Polyplexes containing only poly-L-lysine and DNA aggregated in physiological saline at all charge ratios and aggregated at neutral charge ratios in water. Attachment of asialoorosomucoid lessened, but did not eliminate, the aggregation of PLL polyplexes, and did not result in efficient delivery of polyplexes to hepatocytes. Conjugation of polyethylene glycol to poly-L-lysine sterically stabilized resulting polyplexes at neutral charge ratios by shielding the surfaces. For efficient in vivo gene delivery, polyplexes will need to be sterically stabilized to prevent aggregation and interaction with serum components. ß 0167-4781 / 99 / $^see front matter ß 1999 Published by Elsevier Science B.V. All rights reserved. PII: S 0 1 6 7 -4 7 8 1 ( 9 8 ) 0 0 2 7 4 -
Journal of The American Chemical Society, 1981
Page 1. J. Am. Chem. SOC. 1981, 103, 4691-4696 469 1 NMR Studies of Base-Catalyzed Proton Exchang... more Page 1. J. Am. Chem. SOC. 1981, 103, 4691-4696 469 1 NMR Studies of Base-Catalyzed Proton Exchange in Amides Charles L. Perrin,* Eric R. Johnston, Charles Peter Lollo, and Paul A. Kobrin Contribution from the Department ...
Journal of Labelled Compounds & Radiopharmaceuticals, 1978
2-Methylpropionic, n-butyric, 2-methylbutyric and n-heptanoic acids labelled with 13C or 2H at va... more 2-Methylpropionic, n-butyric, 2-methylbutyric and n-heptanoic acids labelled with 13C or 2H at various positions were synthesized. Carbon-13 was introduced to the carboxyl group by Grignard synthesis. Malonate ester synthesis was utilized to introduce labelled methyl group(s) at 2-position of the branched acids. Procedures for small scale synthesis by these commonly used methods are described in detail. In addition, a novel method for the introduction of a deuterium at the 2-position of these car-boxylic acids by decarboxylation of the corresponding carboxyl-deuterated malonic acid is described.
Expert Opinion on Biological Therapy, 2001
Chronic viral hepatitis is a major clinical problem, with over half a billion persons infected wo... more Chronic viral hepatitis is a major clinical problem, with over half a billion persons infected worldwide. Current therapies, principally treatment with recombinant IFN-alpha protein, have limited benefit. Recent studies suggest that gene-based expression of IFN-alpha is a possible therapeutic alternative that may improve the effectiveness of treatment. Gene delivery to the liver and consequent IFN-alpha expression therein, has the potential to concentrate the protein at the target organ and provide more continuous exposure to the therapeutic agent. Other potential gene and nucleic acid therapeutics for viral hepatitis are also being investigated. Key to the deployment of these future therapies is a suitable method of gene delivery. Although recombinant viral vector systems, such as adenovirus, are currently the most effective means of gene delivery to the liver, their use presents many concerns. These include immune and inflammatory reactions to the viral vector and possible adverse interactions between the recombinant virus and the pre-existing viral infection. Non-viral gene delivery systems would be a preferred treatment modality. The efficiency of current non-viral systems is not adequate for systemically administered liver gene therapy. However, recent use of membrane permeabilisation techniques has shown that high efficiency non-viral gene transfer agents are possible. The future coupling of these improved delivery systems with gene- or nucleic acid-based therapeutics currently in development holds out great promise for new generations of antihepatitis therapies.
Nucleic Acids Research, 1998
The atomic force microscope (AFM) was used to assay the extent of DNA condensation in ∼100 differ... more The atomic force microscope (AFM) was used to assay the extent of DNA condensation in ∼100 different complexes of DNA with polylysine (PL) or PL covalently attached to the glycoproteins asialoorosomucoid (AsOR) or orosomucoid (OR). The best condensation of DNA was obtained with 10 kDa PL covalently attached to AsOR, at a lysine:nucleotide (Lys:nt) ratio of 5:1 or higher. These conditions produce large numbers of toroids and short rods with contour lengths of 300-400 nm. Some DNA condensation into shortened thickened structures was seen with 10 kDa PL attached to AsOR at Lys:nt ratios of 1.6:1 and 3:1. Some DNA condensation was also seen with 4 kDa PL at Lys:nt ratios of 3:1 and higher. Little DNA condensation was seen with PL alone or with PL convalently attached to OR at Lys:nt ratios up to 6:1. AsOR-PL enhanced gene expression in the mouse liver ∼10to 50-fold as compared with PL alone.
Radiation Research, 1995
High-dose radiation therapy for liver metastases of gastrointestinal malignancies might be improv... more High-dose radiation therapy for liver metastases of gastrointestinal malignancies might be improved by combining external-beam irradiation and radioimmunoglobulin therapy. We studied the liver toxicity of the proposed combination in healthy beagle dogs. A total dose of 30 Gy to the whole liver, delivered in 2-Gy fractions over 3 weeks, resulted in mild, temporary veno-occlusive disease (VOD) in three of three dogs. Reversible bone marrow damage was noted after two intravenous injections of 18.5 MBq of yttrium-90-labeled monoclonal antibody ZCE025 per kg body weight in three of three dogs. Administrations of the antibody were separated by 1 week. Three dogs treated by irradiation of the liver with radioimmunoglobulin therapy added during the last 2 weeks of the irradiation showed signs of radiation hepatitis (VOD) starting around 35 days after treatment. One dog had a complete recovery, and two dogs were euthanized in a stage of terminal liver failure around day 90 after treatment. Temporary bone marrow damage was observed after the combined treatment, similar to the bone marrow damage observed after radioimmunoglobulin therapy alone. Earlier studies in the same dog model showed that bone marrow is the dose-limiting organ if radioimmunoglobulin therapy is used alone. The addition of irradiation of the liver to radioimmunoglobulin therapy changes the dose-limiting organ from bone marrow to liver. The radiation hepatitis observed in dogs is very similar to that observed in humans and is reflected in early platelet consumption in the irradiated liver plus late elevations of liver enzymes and VOD in central hepatic veins on histological analysis. Future applications of combined liver irradiation and radioimmunoglobulin therapy in humans should use radioimmunoglobulin therapy agents which show minimal uptake by normal liver.
Biochimica Et Biophysica Acta-general Subjects, 2000
In vitro assays have demonstrated the capability of poly-L-lysine to protect plasmid DNA from ser... more In vitro assays have demonstrated the capability of poly-L-lysine to protect plasmid DNA from serum nucleases and cellular lysates. Our purpose was to evaluate the stability and potency of poly-L-lysine^DNA polyplexes after intravenous injection into mice. Polyplexes consisted of 32 P-radiolabeled plasmid DNA complexed with poly-L-lysine at specified charge ratios. Variations in conjugate hydrophobicity and levels of modification with polyethylene glycol were investigated. Our results show that, in contrast to in vitro studies, the systemically administered polyplexes exhibited marked DNA degradation in the vascular compartment within 5 min. Substitution of poly-L-lysine O-amino sites with polyethylene glycol or hydrocarbon chains resulted in faster degradation even when complexed at higher charge ( þ ) ratios. Use of excess cationic charge in the polyplexes ( þ 2.5) diminished degradation rates only slightly. An analysis was made of the strength of the poly-L-lysine:DNA interaction by competition with poly-aspartic acid. Polyplexes with the strongest binding between conjugate and DNA in the competition assay were also the most stable in blood. However, tighter binding was not enough to fully protect the polyplex in vivo and polyplex DNA was substantially degraded within 10 min. Increased polyplex stability did not correlate with improved in vivo transfection efficiency. ß
Nuclear Medicine Communications, 1994
High background activity produces imaging problems when scanning with antibodies. The following w... more High background activity produces imaging problems when scanning with antibodies. The following work is directed towards reducing this background. The murine monoclonal antibody (MAb) CHA-255 selectively binds 111In-nitrobenzyl EDTA, a molecule referred to as a 'hapten'. Balb/c mice studies indicate that if the antibody is administered prior to the hapten, it predictably modifies the biodistribution and pharmacokinetics of the hapten. The pharmacokinetics for the hapten were proportional to antibody dose and inversely proportional to the time interval between injection of the antibody and the hapten. A hybrid MAb was produced by the enzymatic digestion of CHA-255 and ZCE-025, an anticarcinoembryonic antigen (CEA) MAb, followed by joining of the two via a thioether linkage. The result was a F(ab')2 with affinity for both CEA and the hapten. The pharmacokinetics of the hapten were again dependent upon the kinetics and distribution of the hybrid antibody. Data in tumour models are also presented for 111In-nitrobenzyl EDTA and 111In-thioureabenzyl EDTA (TUBE), a newer hapten. The data indicate that the antibody-hapten system is capable of targeting tumour quickly while normal tissue rapidly becomes depleted of radioactivity. We conclude that the hapten-antibody technique shows some advantages over directly labelled MAb as a targeting system.
International Journal of Radiation Oncology Biology Physics, 1986
A new radiolabel 90Yttrium has been chelated to antiferritin antibodies for the treatment of hepa... more A new radiolabel 90Yttrium has been chelated to antiferritin antibodies for the treatment of hepatocellular cancer. The isotope 90Yttrium has the advantage of no significant external radiation to other individuals, that is, outpatient therapy and potentially more therapeutic power with an increase from 0.3 Mev 131I beta radiation to 0.9 Mev 90Yttrium pure beta radiation. Six patients treated in the Phase I study have had modest hematologic toxicity and two have had partial remissions of their primary tumors. One of these patients has had complete remission of a pulmonary metastasis. The use of external radiation (900 rad) to the primary tumor in advance of radiolabeled antibody administration has increased antibody uptake and increased tumor dose rate and total dose. An extensive study of 90Yttrium antiferritin is planned.
Journal of Macromolecular Science, Part A, 1999
... MARIUSZ G. BANASZCZYK,* CHARLES P. LOLLO, DEBORAH Y. KWOH, ALISON T. PHILLIPS, ARJANG AMINI, ... more ... MARIUSZ G. BANASZCZYK,* CHARLES P. LOLLO, DEBORAH Y. KWOH, ALISON T. PHILLIPS, ARJANG AMINI, DUNCAN P. WU, PATRICIA M. MULLEN ... washed 2x by placing on a distilled water droplet for 15 seconds followed by thoroughly removingliquid by wicking to filter. ...