This is a grant renewal application for the study of controlled release of high molecular weight (MW > 1,000 Daltons) drugs such as polypeptides. The genesis of this work dates to 1979 and involves a systematic study of physical and chemical methods to achieve controlled release of large molecules. During the most recent grant period (1989-91) the investigators synthesized and examined a new class of polymers-poly amino acids linked by non-amide bonds, and initiated fundamental studies of protein inactivation under therapeutically relevant conditions.The protein inactivation work involved three model proteins, insulin (MW 6,000), RNAase (MW 14,000) and hemoglobin (MW 68,000) and examined the issues of aggregation due to wetting, the effect of additives on the extent of protein insolubilization upon wetting, and evaluated the physico-chemical changes in proteins upon wetting. The present proposal intends to study:1) stability of therapeutic proteins in the solid state; and 2) stability of therapeutic proteins in solution. Understanding the fundamental mechanism of how proteins inactivate in these two conditions is fundamental to the fabrication and use of controlled release systems for protein drugs. These mechanistic studies will be aided by mathematical modelling, especially of protein folding and unfolding and will provide insight as to the driving forces for stability/instability of these agents. Specifically the work will examine: 1) aggregation in protein solutions, and 2) solid state stability.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM026698-16
Application #
2174766
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Project Start
1979-07-01
Project End
1996-06-30
Budget Start
1995-04-01
Budget End
1996-06-30
Support Year
16
Fiscal Year
1995
Total Cost
Indirect Cost
Name
Massachusetts Institute of Technology
Department
Engineering (All Types)
Type
Schools of Engineering
DUNS #
City
Cambridge
State
MA
Country
United States
Zip Code
02139
Schroeder, Avi; Goldberg, Michael S; Kastrup, Christian et al. (2012) Remotely activated protein-producing nanoparticles. Nano Lett 12:2685-9
Devitt, Gerard; Thomas, Mini; Klibanov, Alexander M et al. (2007) Optimized protocol for the large scale production of HIV pseudovirions by transient transfection of HEK293T cells with linear fully deacylated polyethylenimine. J Virol Methods 146:298-304
Thomas, Mini; Lu, James J; Zhang, Chengcheng et al. (2007) Identification of novel superior polycationic vectors for gene delivery by high-throughput synthesis and screening of a combinatorial library. Pharm Res 24:1564-71
Sharma, Vikas K; Klibanov, Alexander M (2007) Moisture-induced aggregation of lyophilized DNA and its prevention. Pharm Res 24:168-75
Berry, David; Lynn, David M; Berry, Eric et al. (2006) Heparin localization and fine structure regulate Burkitt's lymphoma growth. Biochem Biophys Res Commun 348:850-6
Thomas, Mini; Ge, Qing; Lu, James J et al. (2005) Cross-linked small polyethylenimines: while still nontoxic, deliver DNA efficiently to mammalian cells in vitro and in vivo. Pharm Res 22:373-80
Sharma, Vikas K; Thomas, Mini; Klibanov, Alexander M (2005) Mechanistic studies on aggregation of polyethylenimine-DNA complexes and its prevention. Biotechnol Bioeng 90:614-20
Colombo, Gaia; Padera, Robert; Langer, Robert et al. (2005) Prolonged duration local anesthesia with lipid-protein-sugar particles containing bupivacaine and dexamethasone. J Biomed Mater Res A 75:458-64
Berry, David; Lynn, David M; Sasisekharan, Ram et al. (2004) Poly(beta-amino ester)s promote cellular uptake of heparin and cancer cell death. Chem Biol 11:487-98
Haining, W Nicholas; Anderson, Daniel G; Little, Steven R et al. (2004) pH-triggered microparticles for peptide vaccination. J Immunol 173:2578-85

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