PEGylated TNF-related apoptosis-inducing ligand (TRAIL)-loaded sustained release PLGA microspheres for enhanced stability and antitumor activity.
The purpose of this work was to develop an effective PEGylated TNF-related apoptosis-inducing ligand (PEG-TRAIL) delivery system for antitumor therapy based on local injection to tumor sites that has a sustained effect without protein aggregation or an initial release burst. The authors designed poly (lactic-co-glycolic) acid (PLGA) microspheres that deliver PEG-TRAIL locally and continuously at tumor sites with sustained biological activity and compared its performance with that of TRAIL microspheres. TRAIL or PEG-TRAIL was microencapsulated into PLGA microspheres using a double-emulsion solvent extraction method. Prepared TRAIL and PEG-TRAIL microspheres showed entirely spherical, smooth surfaces. However, PEG-TRAIL microspheres exhibited a 2.07-fold higher encapsulation efficiency than TRAIL microspheres, and exhibited a tri-phasic in vitro release profile with a lower initial burst (15.8%) than TRAIL microspheres (42.7%). Furthermore, released PEG-TRAIL showed a continued ability to induce apoptosis over 14 days. In vivo pharmacokinetic studies also demonstrated that PEG-TRAIL microspheres had a sustained release profile (18 days), and that the steady-state concentration of PEG-TRAIL in rat plasma was reached at day 3 and maintained until day 15; its steady-state concentration in rat plasma changed from 1444.3 ± 338.4 to 2697.7 ± 419.7 pg/ml. However, TRAIL microspheres were released out within 2 days after administration. Finally, in vivo antitumor tests revealed that tumor growths were significantly more inhibited by a single dose of PEG-TRAIL microspheres than TRAIL microspheres when delivered at 300 μg of TRAIL/mouse. Tumors taken from mouse treated with PEG-TRAIL microspheres showed 78.3% tumor suppression at 24 days, and this was 3.02-fold higher than that observed for TRAIL microspheres (25.9% tumor inhibition). Furthermore, these improved pharmaceutical characteristics of PEG-TRAIL microspheres resulted in superior therapeutic effects without detectable side effects. These findings strongly suggest that PEG-TRAIL microspheres offer a new therapeutic strategy for the treatment of cancers.
College of Pharmacy, SungKyunKwan University, 300 Chonchon-dong, Jangan-ku, Suwon City 440-746, Republic of Korea.
Tae Hyung
TH
Kim
Hai Hua
HH
Jiang
Chan Woong
CW
Park
Yu Seok
YS
Youn
Seulki
S
Lee
Xiaoyuan
X
Chen
Kang Choon
KC
Lee
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use; D003110:Colonic Neoplasms / Q000188:drug therapy*; D003692:Delayed-Action Preparations / Q000737:chemistry*; D045325:HCT116 Cells; D006801:Humans; D019344:Lactic Acid / Q000737:chemistry*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008863:Microspheres; D011092:Polyethylene Glycols / Q000737:chemistry*; D011100:Polyglycolic Acid / Q000737:chemistry*; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D051381:Rats; D017207:Rats, Sprague-Dawley; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use
D000970:Antineoplastic Agents; D003692:Delayed-Action Preparations; D053221:TNF-Related Apoptosis-Inducing Ligand; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D011092:Polyethylene Glycols