Pharmacokinetic and Biodistribution Studies of a Bone-Targeting Drug Delivery System Based onN-(2-Hydroxypropyl)methacrylamide Copolymers

Abstract

Osteotropicity of novel bone-targeted HPMA copolymer conjugates has been demonstrated previously with bone histomorphometric analysis. The pharmacokinetics and biodistribution of this delivery system were investigated in the current study with healthy young BALB/c mice. The 125 Ilabeled bone-targeted and control (non-targeted) HPMA copolymers were administered intravenously to mice and their distribution to different organs and tissues were followed using a gamma counter and single photon emission computed tomography (SPECT). Both the invasive and non-invasive data further confirmed that the incorporation of D-aspartic acid octapeptide (D-Asp 8 ) as bone-targeting moiety could favorably deposit the HPMA copolymers to the entire skeleton, especially to the high bone turnover sites. To evaluate the influence of molecular weight, three fractions (M w of 24, 46, and 96 kDa) of HPMA copolymer -D-Asp 8 conjugate were prepared and evaluated. Higher molecular weight of the conjugate enhanced the deposition to bone due to the prolonged half-life in circulation, but it weakened the bone-selectivity. A higher content of bonetargeting moiety (D-Asp 8 ) in the conjugate is desirable to achieve superior hard tissue selectivity. Further validation of the bone-targeting efficacy of the conjugates in animal models of osteoporosis and other skeletal diseases is needed in the future.

Bisphosphonate-modified biomaterials for drug delivery and bone tissue engineering

“…It can, however, have an adverse effect in terms of specificity to different functional domains of the skeleton. Thus, N-(2-hydroxypropyl)methacrylamide (HPMA) conjugated to D-aspartic acid octapeptide (D-(Asp) 8 ) favorably recognized only resorption sites in skeleton tissues, while its analog carrying Ale moieties directed the polymer to both bone formation and bone resorption sites [36,37]. It was believed that relatively weak binding of D-(Asp) 8 to apatite permitted to differentiate HAP with higher (as in resorption sites) and lower (as in formation sites) crystallinity.…”

Stability in Plasmas of Various Species of HPMA Copolymer–PGE1 Conjugates

“…The increase of content of hydrophobic drug per macromolecule, or the modification of the carrier with hydrophobic stearyl side chains (grafts) resulted in the aggregation of the conjugates, probably to unimolecular micelles, with concomitant increase of their stability. These results, as well as data on bone-binding (40), cathepsin K cleavage (8), and pharmacokinetics and biodistribution (41), suggest that HPMA copolymer-PGE 1 conjugates are strong candidates as novel therapeutics for the treatment of osteoporosis and other musculoskeletal diseases (42,43).…”

Small-Animal SPECT and SPECT/CT: Important Tools for Preclinical Investigation

“…Drugs also may be linked with moieties to guide their targeting or packaged in vehicles for more specific delivery. Small-animal SPECT has been used to identify the migration of 99m Tc-labeled liposomes after intratumoral administration (35) and to study specific skeletal targeting of 125 I-labeled N-(2-hydroxypropyl)methacrylamide copolymer drug-delivery conjugates after intravenous administration (36). SPECT can be included in a multimodality small-animal imaging regimen to compare the location of the vehicle with the location of the drug in vivo.…”