11 results on '"Bolotin EM"'
Search Results
2. Modified C-type natriuretic peptide normalizes tumor vasculature, reinvigorates antitumor immunity, and improves solid tumor therapies.
- Author
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Lu Z, Verginadis I, Kumazoe M, Castillo GM, Yao Y, Guerra RE, Bicher S, You M, McClung G, Qiu R, Xiao Z, Miao Z, George SS, Beiting DP, Nojiri T, Tanaka Y, Fujimura Y, Onda H, Hatakeyama Y, Nishimoto-Ashfield A, Bykova K, Guo W, Fan Y, Buynov NM, Diehl JA, Stanger BZ, Tachibana H, Gade TP, Puré E, Koumenis C, Bolotin EM, and Fuchs SY
- Subjects
- Animals, Mice, Humans, Cell Line, Tumor, Neoplasms drug therapy, Neoplasms pathology, Neoplasms blood supply, Immunity drug effects, Neovascularization, Pathologic drug therapy, Natriuretic Peptide, C-Type pharmacology, Natriuretic Peptide, C-Type therapeutic use, Tumor Microenvironment drug effects
- Abstract
Deficit of oxygen and nutrients in the tumor microenvironment (TME) triggers abnormal angiogenesis that produces dysfunctional and leaky blood vessels, which fail to adequately perfuse tumor tissues. Resulting hypoxia, exacerbation of metabolic disturbances, and generation of an immunosuppressive TME undermine the efficacy of anticancer therapies. Use of carefully scheduled angiogenesis inhibitors has been suggested to overcome these problems and normalize the TME. Here, we propose an alternative agonist-based normalization approach using a derivative of the C-type natriuretic peptide (dCNP). Multiple gene expression signatures in tumor tissues were affected in mice treated with dCNP. In several mouse orthotopic and subcutaneous solid tumor models including colon and pancreatic adenocarcinomas, this well-tolerated agent stimulated formation of highly functional tumor blood vessels to reduce hypoxia. Administration of dCNP also inhibited stromagenesis and remodeling of the extracellular matrix and decreased tumor interstitial fluid pressure. In addition, treatment with dCNP reinvigorated the antitumor immune responses. Administration of dCNP decelerated growth of primary mouse tumors and suppressed their metastases. Moreover, inclusion of dCNP into the chemo-, radio-, or immune-therapeutic regimens increased their efficacy against solid tumors in immunocompetent mice. These results demonstrate the proof of principle for using vasculature normalizing agonists to improve therapies against solid tumors and characterize dCNP as the first in class among such agents.
- Published
- 2024
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3. Subcutaneous therapy for portal hypertension: PHIN-214, a partial vasopressin receptor 1A agonist.
- Author
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Castillo GM, Yao Y, Guerra RE, Jiang H, Nishimoto-Ashfield A, Lyubimov AV, Alfaro JF, Striker KA, Buynov N, Schwabl P, and Bolotin EM
- Subjects
- Humans, Rats, Animals, Receptors, Vasopressin metabolism, Terlipressin, Gastrointestinal Hemorrhage, Vasopressins, Arginine Vasopressin pharmacology, Hyponatremia, Esophageal and Gastric Varices
- Abstract
Cirrhosis is a liver disease that leads to increased intrahepatic resistance, portal hypertension (PH), and splanchnic hyperemia resulting in ascites, variceal bleeding, and hepatorenal syndrome. Terlipressin, a prodrug that converts to a short half-life vasopressin receptor 1 A (V1a) full agonist [8-Lys]-Vasopressin (LVP), is an intravenous treatment for PH complications, but hyponatremia and ischemic side effects require close monitoring. We developed PHIN-214 which converts into PHIN-156, a more biologically stable V1a partial agonist. PHIN-214 enables once-daily subcutaneous administration without causing ischemia or tissue necrosis and has a 10-fold higher therapeutic index than terlipressin in healthy rats. As V1a partial agonists, PHIN-214 and PHIN-156 exhibited maximum activities of 28 % and 42 % of Arginine vasopressin (AVP), respectively. The potency of PHIN-156 and LVP relative to AVP is comparable for V1a (5.20 and 1.65 nM, respectively) and V1b (102 and 115 nM, respectively) receptors. However, the EC
50 of PHIN-156 to the V2 receptor was 26-fold higher than that of LVP, indicating reduced potential for dilutional hyponatremia via V2 agonism compared to terlipressin/LVP. No significant off-target binding to 87 toxicologically relevant receptors were observed when evaluated in vitro at 10 µM concentration. In bile duct ligated rats with PH, subcutaneous PHIN-214 reduced portal pressure by 13.4 % ± 3.4 in 4 h. These collective findings suggest that PHIN-214 could be a novel pharmacological treatment for patients with PH, potentially administered outside of hospital settings, providing a safe and convenient alternative for managing PH and its complications., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: G.M.C., Y.Y., R.E.G., A.N.A., J.A., K.A.S., and E.M.B. are with financial interest as employees of PharmaIN Corp. A.V.L., N.B., and P.S. are advisors to PharmaIN Corp. with financial interest and/or compensation; H.J. is a former employee of PharmaIN Corp. G.M.C., Y.Y, H.J., A.N.A., and E.M.B. have filed the patents related to composition of PHIN-214 with PharmaIN Corp. (WO2022016064A2)., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)- Published
- 2024
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4. Omeprazole and PGC-formulated heparin binding epidermal growth factor normalizes fasting blood glucose and suppresses insulitis in multiple low dose streptozotocin diabetes model.
- Author
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Castillo GM, Nishimoto-Ashfield A, Banerjee AA, Landolfi JA, Lyubimov AV, and Bolotin EM
- Subjects
- Animals, Blood Glucose analysis, Diabetes Mellitus, Experimental pathology, Gastrins pharmacokinetics, Gastrins therapeutic use, Heparin-binding EGF-like Growth Factor, Intercellular Signaling Peptides and Proteins pharmacokinetics, Intercellular Signaling Peptides and Proteins therapeutic use, Male, Mice, Nanostructures chemistry, Omeprazole pharmacokinetics, Omeprazole therapeutic use, Pancreas drug effects, Pancreas pathology, Polymers chemistry, Streptozocin, Diabetes Mellitus, Experimental drug therapy, Drug Carriers chemistry, Gastrins administration & dosage, Intercellular Signaling Peptides and Proteins administration & dosage, Omeprazole administration & dosage
- Abstract
Purpose: Our objective was to develop novel nanocarriers (protected graft copolymer, PGC) that improve the stability of heparin binding EGF (HBEGF) and gastrin and then to use PGC-formulated HBEGF (PGC-HBEGF) and Omeprazole (+/- PGC-gastrin) for normalizing fasting blood glucose (FBG) and improving islet function in diabetic mice., Methods: HBEGF, PGC-HBEGF, Omeprazole, Omeprazole + PGC-HBEGF, Omeprazole + PGC-gastrin + PGC-HBEGF and epidermal growth factor (EGF) + gastrin were tested in multiple low dose streptozotocin diabetic mice., Results: Omeprazole + PGC-HBEGF normalized FBG and is better than EGF + gastrin at improving islet function and decreasing insulitis. Groups treated with Omeprazole, Omeprazole + PGC-HBEGF, or EGF + gastrin have significantly improved islet function versus saline control. All animals that received PGC-HBEGF had significantly reduced islet insulitis versus saline control. Non-FBG was lower for Omeprazole + PGC-gastrin + PGC-HBEGF but Omeprazole + PGC-HBEGF alone showed better FBG and glucose tolerance., Conclusions: Omeprazole + PGC-HBEGF provides a sustained exposure to both EGFRA and gastrin, improves islet function, and decreases insulitis in multiple low dose streptozotocin diabetic mice. Although HBEGF or EGF elevates non-FBG, it facilitates a reduction of insulitis and, in the presence of Omeprazole, provides normalization of FBG at the end of treatment. The study demonstrates Omeprazole and PGC-HBEGF is a viable treatment for diabetes.
- Published
- 2013
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5. Protected graft copolymer excipient leads to a higher acute maximum tolerated dose and extends residence time of vasoactive intestinal Peptide significantly better than sterically stabilized micelles.
- Author
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Reichstetter S, Castillo GM, Rubinstein I, Nishimoto-Ashfield A, Lai M, Jones CC, Banerjee AA, Lyubimov A, Bloedow DC, Bogdanov A Jr, and Bolotin EM
- Subjects
- Animals, Blood Pressure drug effects, Female, Humans, Mice, Mice, Inbred BALB C, Micelles, Vasoactive Intestinal Peptide pharmacology, Vasodilator Agents pharmacology, Drug Carriers chemistry, Excipients chemistry, Vasoactive Intestinal Peptide administration & dosage, Vasoactive Intestinal Peptide pharmacokinetics, Vasodilator Agents administration & dosage, Vasodilator Agents pharmacokinetics
- Abstract
Purpose: To determine and compare pharmacokinetics and toxicity of two nanoformulations of Vasoactive Intestinal Peptide (VIP)., Methods: VIP was formulated using a micellar (Sterically Stabilized Micelles, SSM) and a polymer-based (Protected Graft Copolymer, PGC) nanocarrier at various loading percentages. VIP binding to the nanocarriers, pharmacokinetics, blood pressure, blood chemistry, and acute maximum tolerated dose (MTD) of the formulations after injection into BALB/c mice were determined., Results: Both formulations significantly extend in vivo residence time compared to unformulated VIP. Formulation toxicity is dependent on loading percentage, showing major differences between the two carrier types. Both formulations increase in vivo potency of unformulated VIP and show acute MTDs at least 140 times lower than unformulated VIP, but still at least 100 times higher than the anticipated highest human dose, 1-5 μg/kg. These nanocarriers prevented a significant drop in arterial blood pressure compared to unformulated VIP., Conclusions: While both carriers enhance in vivo residence time compared to unformulated VIP and reduce the drop in blood pressure immediately after injection, PGC is the excipient of choice to extend residence time and improve the safety of potent therapeutic peptides such as VIP.
- Published
- 2013
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6. Protected graft copolymer (PGC) basal formulation of insulin as potentially safer alternative to Lantus® (insulin-glargine): a streptozotocin-induced, diabetic Sprague Dawley rats study.
- Author
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Reichstetter S, Castillo GM, Lai M, Nishimoto-Ashfield A, Banerjee A, Bogdanov A, Lyubimov AV, and Bolotin EM
- Subjects
- Animals, Blood Glucose drug effects, Blood Glucose metabolism, Chemistry, Pharmaceutical methods, Diabetes Mellitus, Experimental metabolism, Drug Carriers administration & dosage, Drug Carriers chemistry, Excipients administration & dosage, Excipients chemistry, Humans, Hypoglycemic Agents chemistry, Insulin Glargine, Male, Rats, Rats, Sprague-Dawley, Receptor, IGF Type 1 metabolism, Diabetes Mellitus, Experimental drug therapy, Hypoglycemic Agents administration & dosage, Insulin, Long-Acting administration & dosage, Insulin, Long-Acting chemistry, Polymers administration & dosage, Polymers chemistry
- Abstract
Purpose: To develop a long-acting formulation of native human insulin with a similar pharmacodynamics (PD) profile as the insulin analogue insulin glargine (Lantus®, Sanofi-Aventis) with the expectation of retaining native human insulin's superior safety profile as insulin glargine is able to activate the insulin-like growth factor 1 (IGF-1) receptor and is linked to a number of malignancies at a higher rate than regular human insulin., Methods: Development of protected graft copolymer (PGC) excipients that bind native human insulin non-covalently and testing blood glucose control obtained with these formulations in streptozotocin-induced diabetic Sprague Dawley rats compared to equally dosed insulin glargine., Results: PGC-formulations of native human insulin are able to control blood glucose to the same extent and for the same amount of time after s.c. injection as the insulin analogue insulin glargine. No biochemical changes were made to the insulin that would change receptor binding and activation with their possible negative effects on the safety of the insulin., Conclusion: Formulation with the PGC excipient offers a viable alternative to biochemically changing insulin or other receptor binding peptides to improve PD properties.
- Published
- 2012
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7. Extending residence time and stability of peptides by protected graft copolymer (PGC) excipient: GLP-1 example.
- Author
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Castillo GM, Reichstetter S, and Bolotin EM
- Subjects
- Animals, Delayed-Action Preparations, Dipeptidyl Peptidase 4 metabolism, Dose-Response Relationship, Drug, Exenatide, Fatty Acids chemistry, Glucagon-Like Peptide 1 blood, Glycated Hemoglobin analysis, Humans, Incretins administration & dosage, Incretins blood, Incretins chemistry, Insulin-Secreting Cells drug effects, Peptides administration & dosage, Polyethylene Glycols chemistry, Polylysine chemistry, Protein Stability, Rats, Rats, Sprague-Dawley, Rats, Zucker, Venoms administration & dosage, Diabetes Mellitus drug therapy, Excipients chemistry, Glucagon-Like Peptide 1 administration & dosage, Glucagon-Like Peptide 1 chemistry
- Abstract
Purpose: To determine whether a Protected Graft Copolymer (PGC) containing fatty acid can be used as a stabilizing excipient for GLP-1 and whether PGC/GLP-1 given once a week can be an effective treatment for diabetes., Methods: To create a PGC excipient, polylysine was grafted with methoxypolyethyleneglycol and fatty acid at the epsilon amino groups. We performed evaluation of the binding of excipient to GLP-1, the DPP IV sensitivity of GLP-1 formulated with PGC as the excipient, the in vitro bio-activity of excipient-formulated GLP-1, the in vivo pharmacokinetics of excipient-formulated GLP-1, and the efficacy of the excipient-formulated GLP-1 in diabetic rats., Results: We showed reproducible synthesis of PGC excipient, high affinity binding of PGC to GLP-1, slowed protease degradation of excipient-formulated GLP-1, and that excipient-formulated GLP-1 induced calcium influx in INS cells. Excipient-formulated GLP-1 stays in the blood for at least 4 days. When excipient-formulated GLP-1 was given subcutaneously once a week to diabetic ZDF rats, a significant reduction of HbA1c compared to control was observed. The reduction is similar to diabetic ZDF rats given exendin twice a day., Conclusions: PGC can be an ideal in vivo stabilizing excipient for biologically labile peptides.
- Published
- 2012
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8. A novel liposomal bupivacaine formulation to produce ultralong-acting analgesia.
- Author
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Grant GJ, Barenholz Y, Bolotin EM, Bansinath M, Turndorf H, Piskoun B, and Davidson EM
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- Adult, Ammonium Sulfate chemistry, Anesthetics, Local adverse effects, Bupivacaine adverse effects, Chemistry, Pharmaceutical, Delayed-Action Preparations, Drug Carriers, Drug Compounding, Humans, Injections, Intradermal, Liposomes, Male, Pain Measurement drug effects, Particle Size, Anesthetics, Local administration & dosage, Anesthetics, Local therapeutic use, Bupivacaine administration & dosage, Bupivacaine therapeutic use
- Abstract
Background: Currently available local anesthetics have relatively brief durations of action. An ultralong-acting local anesthetic would benefit patients with acute and chronic pain. The authors prepared and characterized a novel liposomal bupivacaine formulation using remote loading of bupivacaine along an ammonium sulfate gradient and assessed its efficacy in humans., Methods: A large multivesicular liposomal bupivacaine formulation was prepared by subjecting small unilamellar vesicles to successive freeze-and-thaw cycles. Bupivacaine hydrochloride was then remotely loaded into the liposomes along an ammonium sulfate gradient ([(NH4)2SO4)]intraliposome/[(NH4)2SO4)]medium > 1000). The liposomes were then characterized for size distribution; drug-to-phospholipid ratio; in vitro release profile at 4 degree, 21 degree C, and 37 degree C; sterility; and pyrogenicity. Six subjects each received six intradermal injections in the lower back with 0.5 ml of 0.5, 1.0, and 2% liposomal bupivacaine; 0.5% standard bupivacaine; saline; and "empty" liposomes. Duration of analgesia was assessed using pinprick testing of the skin directly over the injection sites. Results were compared using the log-rank test., Results: The mean large multivesicular vesicle size was 2439 +/- 544 nm, with a drug-to-phospholipid ratio of 1.8, fivefold greater than results previously reported. In vitro release was slowest at 4 degree C. The median duration of analgesia with 0.5% standard bupivacaine was 1 h. The median durations of analgesia after 0.5, 1.0, and 2.0% liposomal bupivacaine were 19, 38, and 48 h, respectively. Neither saline nor "empty" liposomes produced analgesia., Conclusions: This novel liposomal formulation had a favorable drug-to-phospholipid ratio and prolonged the duration of bupivacaine analgesia in a dose-dependent manner. If these results in healthy volunteers can be duplicated in the clinical setting, this formulation has the potential to significantly impact the management of pain.
- Published
- 2004
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9. DRV liposomal bupivacaine: preparation, characterization, and in vivo evaluation in mice.
- Author
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Grant GJ, Barenholz Y, Piskoun B, Bansinath M, Turndorf H, and Bolotin EM
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- Anesthetics, Local pharmacokinetics, Anesthetics, Local pharmacology, Animals, Buffers, Bupivacaine pharmacokinetics, Bupivacaine pharmacology, Capsules, Chemical Phenomena, Chemistry, Physical, Drug Carriers, Drug Compounding, Injections, Subcutaneous, Liposomes, Male, Membranes, Artificial, Mice, Pain Measurement drug effects, Particle Size, Solvents, Anesthetics, Local administration & dosage, Bupivacaine administration & dosage
- Abstract
Purpose: To evaluate the dehydration-rehydration technique to prepare a formulation of liposomal bupivacaine, and to assess its analgesic efficacy., Methods: Bupivacaine hydrochloride (BUP) was encapsulated into dehydration-rehydration vesicles (DRV) of varying phospholipid (PL) compositions. Two bilayer-forming phospholipids were used, the "fluid" dimyristoyl-phosphatidylcholine and the "solid" distearoyl-phosphatidylcholine (DSPC), with 20 or 40 mol% cholesterol, in the presence of bupivacaine at a 1.28 or 0.64 BUP/PL mole ratio. After rehydration, drug/lipid ratios were determined. The formulation with the highest drug/lipid ratio (DSPC/cholesterol in an 8:2 mole ratio prepared in the presence of bupivacaine in a 1.28 BUP/PL mole ratio) was adjusted to a final bupivacaine concentration of 3.5% or 0.5%. The duration of skin analgesia after subcutaneous injection in mice produced by these formulations was compared with the conventional administration of a plain 0.5% solution of BUP. In addition, the concentration of residual bupivacaine at the injection site was followed for 96 h., Results: The relatively low organic solvent/aqueous phase and membrane/aqueous phase partition coefficients, together with liposomal trapped volume and BUP/PL mole ratio, indicated that most of the drug was encapsulated in the intraliposome aqueous phase of the DRV. The DSPC/cholesterol 8:2 mole ratio had the best drug encapsulation (BUP/PL = 0.36). Compared to plain BUP, these BUP-DRV produced significant prolongation of analgesia, which is explained by longer residence time of the drug at the site of injection., Conclusions: Bupivacaine-DRV may have a role in achieving safe, effective, and prolonged analgesia in humans.
- Published
- 2001
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10. Targeted delivery of doxorubicin via sterically stabilized immunoliposomes: pharmacokinetics and biodistribution in tumor-bearing mice.
- Author
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Emanuel N, Kedar E, Bolotin EM, Smorodinsky NI, and Barenholz Y
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- Animals, Antibiotics, Antineoplastic pharmacokinetics, Biological Availability, Doxorubicin pharmacokinetics, Drug Carriers, Female, Liposomes chemistry, Liposomes immunology, Mice, Mice, Inbred BALB C, Neoplasm Transplantation, Stereoisomerism, Tissue Distribution, Tumor Cells, Cultured, Antibiotics, Antineoplastic administration & dosage, Doxorubicin administration & dosage, Fibrosarcoma metabolism, Lung Neoplasms metabolism
- Abstract
Purpose: To evaluate benefits in tumor localization, availability, and noncancerous organ distribution of doxorubicin (DOX) delivered via small (< or = 120 nm) sterically stabilized immunoliposomes targeted against a tumor-associated antigen in fibrosarcoma-bearing mice., Methods: DOX-loaded liposomes were prepared with (i) specific monoclonal IgG3 antibody (32/2, D-SSIL-32/2); (ii) non-specific IgG3 (D-SSIL-IgG); or (iii) no IgG (D-SSL) on their surface. Equal DOX amounts were injected intravenously via each type of liposome into BALB/c mice carrying experimental lung metastases of a polyoma virus-induced fibrosarcoma (A9 ctc 220) expressing a polyoma virus-induced tumor-associated antigen (PAA) on their surface. Metastases occurred mainly in lung. Mice were treated at 3 stages of tumor development (micrometastases, medium-size metastases, and large, necrotic metastases). Performance evaluation was based on time-dependent quantification of DOX and DOX metabolites (DOX-M) in lung tumor, noncancerous organs, and plasma., Results: (i) DOX delivered via both SSIL retained the prolonged circulation time typical of DOX delivered via D-SSL. (ii) DOX accumulation in noncancerous organs was similar for all preparations. Low levels of DOX-M were obtained for all three preparations in all organs except liver, suggesting a similar processing. (iii) Preparations differed in behavior in lung tumor depending on tumor size and microanatomy. Only at the micrometastases stage were the specifically targeted D-SSIL-32/2 superior to D-SSL and D-SSIL-IgG, delivering 2-4 times more drug into the tumor. (iv) DOX-M level in all three tumor stages was in the following order: D-SSIL-32/2 > > D-SSL > > D-SSIL-IgG, suggesting that DOX delivered as D-SSIL-32/2 is most available to tumor cells., Conclusions: The advantage of specific targeting of sterically stabilized liposomes is expressed mainly in increasing availability of DOX to tumor cells in a way which is dependent on tumor microanatomy. The impact of this advantage to therapeutic efficacy remains to be determined.
- Published
- 1996
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11. Preparation and characterization of doxorubicin-loaded sterically stabilized immunoliposomes.
- Author
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Emanuel N, Kedar E, Bolotin EM, Smorodinsky NI, and Barenholz Y
- Subjects
- Animals, Antibodies, Monoclonal pharmacokinetics, Chemistry, Pharmaceutical, Doxorubicin pharmacokinetics, Drug Carriers, Drug Compounding, Drug Stability, Female, Immunoconjugates administration & dosage, Immunoconjugates metabolism, Immunoglobulin G metabolism, Liposomes, Macrophages, Peritoneal metabolism, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Sensitivity and Specificity, Tissue Distribution, Doxorubicin administration & dosage, Immunoconjugates pharmacokinetics
- Abstract
Purpose: To compare the performance of sterically stabilized, doxorubicin-loaded liposomes with and without surface attached specific antibodies (D-SSIL and D-SSL, respectively)., Methods: Small (< or = 120 nm) unilamellar liposomes were prepared composed of hydrogenated soy phosphatidylcholine, hydrogenated phosphatidylethanolamine (HPE), cholesterol, and 2000Da polyethylene glycol (2000PEG) attached to the primary amino group of distearoyl phosphatidylethanolamine. Doxorubicin was remote-loaded into these liposomes by an ammonium sulfate gradient to form the D-SSL. Monoclonal IgG3 NI32/2 antibodies directed against a polyoma virus tumor-associated antigen expressed on A9 ctc 102 murine fibrosarcoma cells were attached to the D-SSL HPE via a thioether bond to form the D-SSIL-32/2. A control of nonspecific D-SSIL was prepared by attaching nonspecific IgG3-enriched immunoglobulins to D-SSL. All liposomes were physically and chemically characterized and then tested in vitro for tumor cell binding, specificity, and uptake by macrophages; and in vivo for the drug plasma pharmacokinetics after intravenous administration in mice., Results: (i) The attachment of antibodies to D-SSL did not impair their chemical or physical stability and had a minimal effect on their size and level of loaded drug. (ii) The combination of specific antibodies and 2000PEG grafted in the liposomes improved the specific binding to relevant target cells by reducing the level of unspecific binding to nonrelevant cells. (iii) D-SSIL retained the prolonged circulation and slow clearance typical of SSL lacking the antibodies., Conclusions: Sterically stabilized immunoliposomes exhibited stability, ability to recognize target cells, and prolonged circulation time. This study also shows that it is feasible to prepare them in pharmaceutically acceptable dosage form. Thus, further investigation for tumor targeting and efficacy is warranted.
- Published
- 1996
- Full Text
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