Biopolymer-based delivery systems for advanced imaging and skeletal tissue-specific therapeutics

Abstract

There is considerable advantage in developing tissue-specific delivery systems for therapeutic and diagnostic applications. Synthetic water-soluble polymeric delivery systems have been developed to allow selective delivery of therapeutic and imaging agents to musculoskeletal tissues. For mineralized tissues, bone-targeting agents such as aspartic acid octapeptide could concentrate the polymer conjugates to bone surfaces including resorption sites, which was demonstrated with routine bone histomorphometry. For bone-associated soft tissues, other targeting approaches based on pathophysiological properties unique to the local tissue environment, such as the leaky vasculature in arthritic joints, were utilized to achieve the selective deposition of the polymeric delivery systems to the desired sites. For this study, magnetic resonance imaging (MRI) was used to assess real-time pharmacokinetics and biodistribution of the MRI contrast agent conjugated polymer in major organs including skeletal tissues. The MRI data were then correlated with other standard imaging methods such as pQCT and DXA as well as routine histopathology and skeletal histomorphometry. Clearly, biopolymeric delivery systems may be used to improve the pharmacological and pharmacokinetic properties of different therapeutic agents for musculoskeletal diseases such as osteoporosis and arthritis. In addition, this or related technologies may also be useful to improve diagnosis and medical imaging with positron emission tomography, gamma scintigraphy, or other technologies.

Feasibility of Using a Bone-Targeted, Macromolecular Delivery System Coupled with Prostaglandin E1 to Promote Bone Formation in Aged, Estrogen-Deficient Rats

“…We have previously demonstrated that Asp 8 or bisphosphonate conjugates of HPMA copolymers are readily incorporated into bone (6). Interestingly, however, the HPMA copolymer–Asp 8 conjugates were found in initial studies in mice to show preferential uptake on resorption surfaces (7) and a similar observation was made in the present study in aged, ovx rats. The osteotropicity of the hexapeptide of aspartic acid (Asp 6 ) was first described by Kasugai et al (19) and later this group conjugated Asp 6 to estradiol and found that the conjugate maintained a positive bone effect but minimized other side effects when compared with unconjugated estradiol (20).…”

“…Newly formed bone usually has a lower crystallinity than older bone and it is the older bone that is usually undergoing bone resorption (22). This may help explain why there was uptake of bisphosphonate-HPMA copolymer–FITC conjugates on both formation and resorption surfaces (7), whereas there was better relative uptake of Asp 8 -HPMA copolymer–FITC conjugates on resorption surfaces where more mature bone with a higher crystallinity would be exposed. This difference may provide a valuable and unique opportunity to target therapeutics to different functional bone surfaces.…”

“…These macromolecular therapeutic systems are based on N -(2-hydroxypropyl)methacrylamide (HPMA) copolymers. The HPMA copolymer system can be selectively targeted to bone by attaching a bone-seeking compound, such as a bisphosphonate or d -aspartic acid peptides (6,7), although other molecules may also have activity (2). We have also recently demonstrated that HPMA copolymer conjugated with d -aspartic acid octapeptide (Asp 8 ) have some preferential uptake on resorption surfaces compared with HPMA copolymer conjugated with a bisphosphonate (8).…”