Development and characterization of interleukin-18-loaded biodegradable microspheres.
Immunostimulation represents a promising approach designed to specifically eradicate malignant cells. Since glioma tumour cells hole up in the central nervous system (CNS) in a particularly inauspicious milieu to antitumour immune reactions we here propose a new strategy to revert the properties of this microenvironment by administering an antitumour cytokine into the CNS tumour itself. Thus, biodegradable poly(D,L-lactide-co-glycolide) (PLGA) sustained-release microspheres for stereotaxic implantation loaded with interleukin-18 (IL-18), that is known to exert antitumour activity and trigger immune cell-mediated cytotoxicity, were developed. Different tests for assessing IL-18 bioactivity were set-up and evaluated. A specific bioassay was considered as the most reliable test. The stability and integrity of IL-18 was then verified during the encapsulation process. Consequently, two procedures of IL-18 encapsulation in PLGA microparticles (W/O/W and S/O/W) were investigated. As determined by radiolabelling studies using 125I-IL-18 and a continuous flow system, the in vitro release profile of IL-18 was optimum with S/O/W method with a moderate burst effect and a subsequent progressive discharge of 16.5+/-8.4 ng/day during the next 21 days against 6.1+/-4.2 ng/day with the W/O/W method. Considering analytical testing of IL-18 together with its preserved biological activity after release from microspheres, amounts of the active cytokine obtained with S/O/W method were relevant to plan in vivo evaluation to validate the therapeutic strategy.
Lagarce
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Inserm, U646, 10 rue André Boquel, F-49100 Angers, France.
Garcion
E
E
Faisant
N
N
Thomas
O
O
Kanaujia
P
P
Menei
P
P
Benoit
J P
JP
D020341:Absorbable Implants; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D002478:Cells, Cultured; D004337:Drug Carriers; D004343:Drug Implants; D004355:Drug Stability; D005910:Glioma / Q000188:drug therapy*; D007371:Interferon-gamma / Q000378:metabolism; D020382:Interleukin-18 / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D019344:Lactic Acid / Q000737:chemistry*; D008863:Microspheres; D011092:Polyethylene Glycols / Q000737:chemistry; D011100:Polyglycolic Acid / Q000737:chemistry*; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011108:Polymers / Q000737:chemistry*; D051381:Rats; D012710:Serum Albumin, Bovine / Q000737:chemistry; D012995:Solubility; D013154:Spleen / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D013678:Technology, Pharmaceutical / Q000379:methods
D000970:Antineoplastic Agents; D004337:Drug Carriers; D004343:Drug Implants; D020382:Interleukin-18; D011108:Polymers; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D012710:Serum Albumin, Bovine; D019344:Lactic Acid; D011092:Polyethylene Glycols; D007371:Interferon-gamma