We propose and study in and in vivo a new family micellar drug carriers with controlled longevity, biodistribution, and target ability. Studies on biological pharmacological properties of various micelles have revealed their high potential as drug carriers for sparingly soluble pharmaceuticals. However, routinely used micelles have insufficient stability upon dilution and in vivo, or require chemical attache of a drug to a hydrophobic moiety of a micelle-forming surfactant molecule. Based on our preliminary experiments with new highly stable micelles prepared from diacyllipidpolyethyleneoxide (PEO) conjugates, our hypothesis is that lipid-PEO-based micelles (or micelles prepared from lipid conjugates with other PEO-like hydrophilic polymers) stable at physiologic conditions may serve as an efficient delivery system for therapeutic and diagnostic agents, and that the bioavailability of micelle-incorporated poorly soluble drugs may be increased. Targeted delivery of micelle-solubilized pharmaceuticals can be achieved by covalent coupling of specific antibodies to the free ends of hydrophillic. Overall, a proposed drug delivery system should definitely benefit from: 1) properties of PEO or similar polymers as steric protective agents for particulate; 2) extreme stability of diacyllipid-PEO and similar micelles; 3) smaller size compared to other known delivery systems; 4) high solubilization of power of PEO-based surfactants; 5) possibility of targeted delivery. In the present study we propose: a) to synthesize and characterize a set of new micelle-forming copolymers; b) to prepare micelles from these polymers, and to study how micelle stability, size, and ability to retain entrapped substances depend on polymer type, size of hydrophilic block, and loading degree; c) To study the biodistribution and longevity of micelles in mice, and their ability to accumulate in areas with affected vasculature in mice and rabbits; d) to prepare targeted micelles by attachment of a corresponding antibody to a free end of a hydrophilic bloc, and to investigate the properties and target ability of immunomicelles both in vitro and in vivo in infarcted rabbits and tumor (EL4 lymphoma and Lewis lung carcinoma) -bearing mice; e) to perform preliminary experiments on micellar delivery of actual therapeutic and diagnostic agents. As a result of this proposed study we plan to introduce a new family of micellar drug carriers for sparingly soluble pharmaceuticals and to determine the optimum micelle compositions and properties for use as pharmaceutical carriers.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM060200-02
Application #
6181573
Study Section
Pharmacology A Study Section (PHRA)
Program Officer
Cole, Alison E
Project Start
1999-05-01
Project End
2003-04-30
Budget Start
2000-05-01
Budget End
2001-04-30
Support Year
2
Fiscal Year
2000
Total Cost
$213,395
Indirect Cost
Name
Northeastern University
Department
Other Health Professions
Type
Schools of Pharmacy
DUNS #
039318308
City
Boston
State
MA
Country
United States
Zip Code
02115
Wang, Junping; Mongayt, Dmitriy A; Lukyanov, Anatoly N et al. (2004) Preparation and in vitro synergistic anticancer effect of vitamin K3 and 1,8-diazabicyclo[5,4,0]undec-7-ene in poly(ethylene glycol)-diacyllipid micelles. Int J Pharm 272:129-35
Lukyanov, Anatoly N; Hartner, William C; Torchilin, Vladimir P (2004) Increased accumulation of PEG-PE micelles in the area of experimental myocardial infarction in rabbits. J Control Release 94:187-93
Lukyanov, Anatoly N; Gao, Zhonggao; Torchilin, Vladimir P (2003) Micelles from polyethylene glycol/phosphatidylethanolamine conjugates for tumor drug delivery. J Control Release 91:97-102
Asahi, Minoru; Rammohan, Ram; Sumii, Toshihisa et al. (2003) Antiactin-targeted immunoliposomes ameliorate tissue plasminogen activator-induced hemorrhage after focal embolic stroke. J Cereb Blood Flow Metab 23:895-9
Torchilin, Vladimir P; Lukyanov, Anatoly N; Gao, Zhonggao et al. (2003) Immunomicelles: targeted pharmaceutical carriers for poorly soluble drugs. Proc Natl Acad Sci U S A 100:6039-44
Gao, Z; Lukyanov, A N; Chakilam, A R et al. (2003) PEG-PE/phosphatidylcholine mixed immunomicelles specifically deliver encapsulated taxol to tumor cells of different origin and promote their efficient killing. J Drug Target 11:87-92
Lukyanov, Anatoly N; Gao, Zhonggao; Mazzola, Laureen et al. (2002) Polyethylene glycol-diacyllipid micelles demonstrate increased acculumation in subcutaneous tumors in mice. Pharm Res 19:1424-9
Torchilin, V P; Levchenko, T S; Whiteman, K R et al. (2001) Amphiphilic poly-N-vinylpyrrolidones: synthesis, properties and liposome surface modification. Biomaterials 22:3035-44
Lo, E H; Singhal, A B; Torchilin, V P et al. (2001) Drug delivery to damaged brain. Brain Res Brain Res Rev 38:140-8