title: Biocompatibility of poly(D,L-lactic-co-hydroxymethyl glycolic acid) microspheres after subcutaneous and subcapsular renal injection.
abstract: Poly(D,L-lactic-co-hydroxymethyl glycolic acid) (PLHMGA) is a biodegradable copolymer with potential as a novel carrier in polymeric drug delivery systems. In this study, the biocompatibility of PLHMGA microspheres (PLHMGA-ms) was investigated both in vitro in three different cell types (PK-84, HK-2 and PTECs) and in vivo at two implantation sites (by subcutaneous and subcapsular renal injection) in rats. Both monodisperse (narrow size distribution) and polydisperse PLHMGA-ms were prepared with volume weight mean diameter of 34 and 17 μm, respectively. Mono and polydisperse PLHMGA-ms showed good cytocompatibility properties upon 72 h incubation with the cells (100 μg microspheres/600 μL/cell line). A mild foreign body reaction was seen shortly after subcutaneous injection (20 mg per pocket) of both mono and polydisperse PLHMGA-ms with the presence of mainly macrophages, few foreign body giant cells and myofibroblasts. This transient inflammatory reaction diminished within 28 days after injection, the time-point at which the microspheres were degraded. The degradation profile is comparable to the in vitro degradation time of the microspheres (i.e., within 35 days) when incubated at 37 °C in phosphate buffered saline. Subcapsular renal injection of monodisperse PLHMGA-ms (10 mg) in rats was characterized with similar inflammatory patterns compared to the subcutaneous injection. No cortical damage was observed in the injected kidneys. In conclusion, this study demonstrates that PLHMGA-ms are well tolerated after in vivo injection in rats. This makes them a good candidate for controlled delivery systems of low-molecular weight drugs as well as protein biopharmaceuticals.
authors.affiliation: Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Universiteitsweg 99, 3584 CG, Utrecht, The Netherlands.
authors.forename: F
authors.initials: F
authors.lastname: Kazazi-Hyseni
authors.affiliation: Department of Pathology and Medical Biology, Medical Biology Section, University Medical Centre Groningen, University of Groningen, Hanzeplein 1, 9713 GZ, Groningen, The Netherlands.
authors.forename: J
authors.initials: J
authors.lastname: Zandstra
authors.affiliation: Department of Pathology and Medical Biology, Medical Biology Section, University Medical Centre Groningen, University of Groningen, Hanzeplein 1, 9713 GZ, Groningen, The Netherlands.
authors.forename: E R
authors.initials: ER
authors.lastname: Popa
authors.affiliation: Department of Pathology, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX, Utrecht, The Netherlands.
authors.forename: R
authors.initials: R
authors.lastname: Goldschmeding
authors.affiliation: Nanomi B.V., Zutphenstraat 51, 7575 EJ, Oldenzaal, The Netherlands.
authors.forename: A A R
authors.initials: AA
authors.lastname: Lathuile
authors.affiliation: Nanomi B.V., Zutphenstraat 51, 7575 EJ, Oldenzaal, The Netherlands.
authors.forename: G J
authors.initials: GJ
authors.lastname: Veldhuis
authors.affiliation: Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Universiteitsweg 99, 3584 CG, Utrecht, The Netherlands.
authors.forename: C F
authors.initials: CF
authors.lastname: Van Nostrum
authors.affiliation: Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Universiteitsweg 99, 3584 CG, Utrecht, The Netherlands.
authors.forename: W E
authors.initials: WE
authors.lastname: Hennink
authors.affiliation: Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Universiteitsweg 99, 3584 CG, Utrecht, The Netherlands. Electronic address: r.j.kok@uu.nl.
authors.forename: R J
authors.initials: RJ
authors.lastname: Kok
mesh_terms: D000279:Administration, Cutaneous; D000818:Animals; D001672:Biocompatible Materials / Q000008:administration & dosage* / Q000009:adverse effects; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D004337:Drug Carriers / Q000008:administration & dosage* / Q000009:adverse effects; D004355:Drug Stability; D005549:Foreign-Body Reaction / Q000139:chemically induced / Q000473:pathology; D007668:Kidney / Q000187:drug effects* / Q000473:pathology; D008297:Male; D008863:Microspheres; D011091:Polyesters / Q000008:administration & dosage* / Q000009:adverse effects; D051381:Rats
chemical_list: D001672:Biocompatible Materials; D004337:Drug Carriers; D011091:Polyesters; C576815:poly(lactide-co-hydroxymethyl glycolide)
keywords: Biocompatibility; Cytocompatibility; Monodisperse microspheres; PLHMGA