Suresh Bhatia
Princeton University
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Biochimica et Biophysica Acta | 1997
Patrick L. Ahl; Suresh Bhatia; Paul Meers; Patricia Roberts; Rachel Stevens; Richard Dause; Walter Perkins; Andrew S. Janoff
Incorporation of N-(omega-carboxy)acylamido-phosphatidylethanolamines (-PEs) into large unilamellar vesicles (LUVs) of L-alpha-distearoylphosphatidylcholine (DSPC) was found to dramatically increase the in vivo liposomal circulation lifetime in rats, reaching a maximal effect at 10 mol.% of the total phospholipid. Neither pure DSPC liposomes nor those with the longest circulating derivative, N-glutaryl-dipalmitoylphosphatidylethanolamine (-DPPE), were found to significantly bind complement from serum. Therefore, the relatively short circulation time of pure DSPC liposomes did not appear to be related to greater complement opsonization leading to uptake by the reticuloendothelial system. However, N-(omega-carboxy)acylamido-PEs were particularly efficient inhibitors of a limited aggregation detected for pure DSPC liposomes. The aggregation tendency of DSPC liposomes incorporating various structural analogs of N-glutaryl-DPPE correlated inversely with the circulation lifetimes. Therefore, it is concluded that such PE derivatives enhance the circulation time by preventing liposomal aggregation and avoiding a poorly understood mechanism of clearance that is dependent on size but is independent of complement opsonization. At high concentrations of N-glutaryl-DPPE (above 10 mol.%), the liposomes exhibited strong complement opsonization and were cleared from circulation rapidly, as were other highly negatively charged liposomes. These data demonstrate that both the lack of opsonization and the lack of a tendency to aggregate are required for long circulation. Liposomal disaggregation via N-(omega-carboxy)acylamido-PEs yields a new class of large unilamellar DSPC liposomes with circulation lifetimes that are comparable to those of sterically stabilized liposomes.
Biochimica et Biophysica Acta | 1997
Eric Mayhew; Imran Ahmad; Suresh Bhatia; Richard Dause; Julius Filep; Andrew S. Janoff; Elizabet Kaisheva; Walter Perkins; Yan Zha; J. Craig Franklin
The ether lipid, 1-O-octadecyl-2-O-methyl-sn-glycero-3-phosphocholine (ET-18-OCH3), has anticancer activity, but it has serious side-effects, including hemolysis, which prevent its optimal use. We surmised if ET-18-OCH3 could be stably associated with liposomes, less free ET-18-OCH3 would be available for lytic interaction with red cells. Liposome composition variables investigated included acyl chain saturation, phospholipid head group and mole ratio of Chol and ET-18-OCH3. It was found that attenuation of hemolysis was strongly liposome composition dependent. Some ET-18-OCH3 liposome compositions were minimally hemolytic. For example, whereas the HI5 (drug concentration required to cause 5% human red cell lysis) was 5-6 microM for free ET-18-OCH3, it was approximately 250 microM for DOPC (dioleoylphosphatidylcholine):Chol (cholesterol):DOPE-GA (glutaric acid derivatized DOPE):ET-18-OCH3, (4:3:1:2) and 640 microM for DOPE (dioleyolphosphatidylethanolamine):Chol:DOPE-GA:ET-18-OCH3 (4:3:1:2) liposomes. Efflux of carboxyfluorescein (CF) from liposomes and Langmuir trough determinations of mean molecular area of lipids in monolayers (MMAM) were used as indicators of membrane packing and stability. Incorporation of ET-18-OCH3 in liposomes reduced the MMAM. Reduction in CF permeation was correlated with reduction in hemolysis. The most stable liposomes included components, such as cholesterol, DOPC and DOPE, which have complementary shapes to ET-18-OCH3.
Archive | 1996
Eric Mayhew; J. Craig Franklin; Suresh Bhatia; Paul A. Harmon; Andrew S. Janoff
Archive | 1998
Eric Mayhew; Andrew S. Janoff; Imran Ahmad; Suresh Bhatia
Archive | 1994
Patrick L. Ahl; Suresh Bhatia; Sharma R. Minchey; Andrew S. Janoff
Archive | 1998
Eric Mayhew; Andrew S. Janoff; Imran Ahmad; Suresh Bhatia
Archive | 1995
Eric Mayhew; Andrew S. Janoff; Imran Ahmad; Suresh Bhatia
Archive | 1996
Eric Mayhew; J. Craig Franklin; Suresh Bhatia; Paul A. Harmon; Andrew S. Janoff
Archive | 1997
Eric Mayhew; J. Craig Franklin; Suresh Bhatia; Paul A. Harmon; Andrew S. Janoff
Archive | 1996
Eric Mayhew; Andrew S. Janoff; Imran Ahmad; Suresh Bhatia