Osteoporosis is a major public health threat. Currently, osteoporosis is present in an estimated 44 million men and women aged 50 and older, which represent 55 percent of the population in that age group in the USA. In addition to the enormous medical costs, this condition leads to a substantial increase in mortality. A new approach for the treatment of osteoporosis and other musculoskeletal diseases is proposed a targeted drug delivery system employing bone targeted; water-soluble polymer conjugates as carriers for the anabolic agent, prostaglandin E1. Previous experiments have demonstrated that D-Asp8-targeted conjugates are preferentially incorporated onto bone resorption surfaces. This offers a unique opportunity to target drugs to sites of active bone resorption. Another encouraging result was the observation that increases in bone formation could be sustained for at least a month following a single injection of the conjugate. The main aim of the proposed research is to design novel, effective conjugates for the treatment of osteoporosis. We designed new, biodegradable N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer conjugates. An important design characteristic is the insertion of degradable bonds into the polymer main chain (backbone). Consequently, a higher molecular weight than with nondegradable carriers may be used, resulting in long circulation times and enhanced accumulation in bone due to leaky vasculature and increased number of targeting moieties per chain. Main features of the new design are as follows: a) The new biodegradable HPMA-based polymeric carrier will be composed of short telechelic HPMA copolymer segments, containing PGE1 and targeting moieties, prepared by RAFT (reversible addition-fragmentation chain transfer) polymerization using an azido-functionalized RAFT chain transfer agent. These segments will be extended into high molecular weight (long-circulating) carriers by a highly efficient click chemistry reaction with enzymatically degradable (acetylene functionalized) oligopeptides; b) The targeting D-Asp8 group will be bound to the polymer backbone via a cathepsin K sensitive spacer; c) PGE1 will be bound to the polymer backbone via an ether bond; it will be connected to the carrier via an 1,6-elimination group and a cathepsin K sensitive spacer. The previously used ester bond was stable in humans, but susceptible to hydrolysis in rat and mouse plasma, which complicated the optimization of the conjugate. The new design will avoid these difficulties. To optimize the therapeutic protocol a dose escalation study, a time sequence study, and a multiple dose study will be performed. Numerous analyses will be performed to determine the effect of the conjugates on various bone indices, namely bone mineral density, bone mineral content, bone biomechanical, biomorphometric, and histomorphometric properties. The concept of (main chain) biodegradable HPMA copolymer drug carriers targeted to bone resorption sites is a new paradigm for the design of efficient drugs for the treatment of musculoskeletal diseases.

Public Health Relevance

The proposal addresses one of the important problems of osteoporosis treatment delivery of (anabolic) drugs to sites of bone resorption. The advantages of the proposed drug delivery systems are: selective adsorption to the tissues in bone with higher rates of bone turnover, localization of the anabolic agent (prostaglandin E1) in skeletal sites where bone formation would be beneficial, the reduction of side-effects resulting from systemic administration of free drugs, and applicability of design principles to the delivery of other drugs. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
2R01GM069847-05
Application #
7526000
Study Section
Bioengineering, Technology and Surgical Sciences Study Section (BTSS)
Program Officer
Okita, Richard T
Project Start
2003-12-01
Project End
2012-07-31
Budget Start
2008-08-01
Budget End
2009-07-31
Support Year
5
Fiscal Year
2008
Total Cost
$301,000
Indirect Cost
Name
University of Utah
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
009095365
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112
Yang, Jiyuan; Kope?ek, Jind?ich (2016) Design of smart HPMA copolymer-based nanomedicines. J Control Release 240:9-23
Low, Stewart A; Galliford, Chris V; Yang, Jiyuan et al. (2015) Biodistribution of Fracture-Targeted GSK3? Inhibitor-Loaded Micelles for Improved Fracture Healing. Biomacromolecules 16:3145-53
Yang, Jiyuan; Kope?ek, Jind?ich (2015) POLYMERIC BIOMATERIALS AND NANOMEDICINES. J Drug Deliv Sci Technol 30:318-330
Low, Stewart A; Yang, Jiyuan; Kope?ek, Jind?ich (2014) Bone-targeted acid-sensitive doxorubicin conjugate micelles as potential osteosarcoma therapeutics. Bioconjug Chem 25:2012-20
Yang, Jiyuan; Kope?ek, Jind?ich (2014) Macromolecular therapeutics. J Control Release 190:288-303
Pan, Huaizhong; Sima, Monika; Miller, Scott C et al. (2013) Efficiency of high molecular weight backbone degradable HPMA copolymer-prostaglandin E1 conjugate in promotion of bone formation in ovariectomized rats. Biomaterials 34:6528-38
Kope?ek, Jind?ich (2013) Polymer-drug conjugates: origins, progress to date and future directions. Adv Drug Deliv Rev 65:49-59
Zhou, Yan; Kope?ek, Jind?ich (2013) Biological rationale for the design of polymeric anti-cancer nanomedicines. J Drug Target 21:1-26
Low, Stewart A; Kopecek, Jindrich (2012) Targeting polymer therapeutics to bone. Adv Drug Deliv Rev 64:1189-204
Pan, Huaizhong; Yang, Jiyuan; Kopeckova, Pavla et al. (2011) Backbone degradable multiblock N-(2-hydroxypropyl)methacrylamide copolymer conjugates via reversible addition-fragmentation chain transfer polymerization and thiol-ene coupling reaction. Biomacromolecules 12:247-52

Showing the most recent 10 out of 25 publications