Development of PTH eluting microspheres for the treatment of hypoparathyroidism.
BACKGROUND
Parathyroid hormone (PTH) replacement has been demonstrated to be superior to conventional treatment with calcium supplementation and vitamin D analogs for the treatment of hypoparathyroidism. In this investigation we evaluated the feasibility of using PTH microsphere encapsulation as a potential delivery system for PTH.


METHODS
Using the spontaneous emulsion technique, PTH microspheres were created by encapsulating PTH (1-34) in a copolymer of polyglycolic and polylactic acid (PLGA). Additional microspheres were constructed by coencapsulating calmodulin with PTH (1-34) in the PLGA microspheres. Microsphere production was confirmed using electron microscopy. PTH release was measured in vitro using an enzyme-linked immunosorbent assay. The bioactivity of PTH released from the microspheres was confirmed in vivo using a hypoparathyroid rat model by measuring serum calcium concentrations before and 3 h after subcutaneous injection of PTH microspheres.


RESULTS
PTH microsphere and PTH/calmodulin microspheres could be created using the spontaneous emulsion technique. Physiologically significant PTH release was measured in vitro for 20 days. PTH release was calcium sensitive and exhibited negative feedback. This effect was augmented by coencapsulation with calmodulin. PTH released from the microspheres caused a significant rise in serum calcium levels from an average of 6.35 (6.19-6.48 mg/dL) to 8.55 mg/dL (8.22-8.73). PTH released from the PTH/calmodulin microspheres resulted in an increase in serum calcium from a mean of 6.8 (6.7-6.9 mg/dL) to 8.1 mg/dL (7.8-8.2).


CONCLUSIONS
The PLGA microspheres can be used to provide calcium sensitive controlled release of biologically active PTH and offer a potential mean of providing biomimetic hormone replacement therapy.
Fong
Peter
P
Department of Surgery, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
Goyal
Amit
A
Brennan
Matthew
M
Park
Jason
J
Moss
Lawrence
L
Saltzman
W Mark
WM
Breuer
Christopher K
CK
D000818:Animals; D002118:Calcium / Q000097:blood; D002147:Calmodulin / Q000494:pharmacology*; D004339:Drug Compounding; D016503:Drug Delivery Systems / Q000379:methods*; D025461:Feedback, Physiological / Q000187:drug effects; D020249:Hormone Replacement Therapy / Q000379:methods*; D007011:Hypoparathyroidism / Q000188:drug therapy*; D007279:Injections, Subcutaneous; D019344:Lactic Acid; D008297:Male; D008855:Microscopy, Electron, Scanning; D008863:Microspheres; D010281:Parathyroid Hormone / Q000494:pharmacology*; D011091:Polyesters; D011100:Polyglycolic Acid; D011108:Polymers; D051381:Rats; D017207:Rats, Sprague-Dawley
D002147:Calmodulin; D010281:Parathyroid Hormone; D011091:Polyesters; D011108:Polymers; D011100:Polyglycolic Acid; D019344:Lactic Acid; C033616:poly(lactide); D002118:Calcium