Modification of polyethylene glycol onto solid lipid nanoparticles encapsulating a novel chemotherapeutic agent (PK-L4) to enhance solubility for injection delivery.
BACKGROUND
The synthetic potential chemotherapeutic agent 3-Chloro-4-[(4-methoxyphenyl) amino]furo[2,3-b]quinoline (PK-L4) is an analog of amsacrine. The half-life of PK-L4 is longer than that of amsacrine; however, PK-L4 is difficult to dissolve in aqueous media, which is problematic for administration by intravenous injection.


OBJECTIVE
To utilize solid lipid nanoparticles (SLNs) modified with polyethylene glycol (PEG) to improve the delivery of PK-L4 and investigate its biodistribution behavior after intravenous administration.


RESULTS
The particle size of the PK-L4-loaded SLNs was 47.3 nm and the size of the PEGylated form was smaller, at 28 nm. The entrapment efficiency (EE%) of PK-L4 in SLNs with and without PEG showed a high capacity of approximately 100% encapsulation. Results also showed that the amount of PK-L4 released over a prolonged period from SLNs both with and without PEG was comparable to the non-formulated group, with 16.48% and 30.04%, respectively, of the drug being released, which fit a zero-order equation. The half-maximal inhibitory concentration values of PK-L4-loaded SLNs with and those without PEG were significantly reduced by 45%-64% in the human lung carcinoma cell line (A549), 99% in the human breast adenocarcinoma cell line with estrogen receptor (MCF7), and 95% in the human breast adenocarcinoma cell line (MDA-MB-231). The amount of PK-L4 released by SLNs with PEG was significantly higher than that from the PK-L4 solution (P < 0.05). After intravenous bolus of the PK-L4-loaded SLNs with PEG, there was a marked significant difference in half-life alpha (0.136 ± 0.046 hours) when compared with the PK-L4 solution (0.078 ± 0.023 hours); also the area under the curve from zero to infinity did not change in plasma when compared to the PK-L4 solution. This demonstrated that PK-L4-loaded SLNs were rapidly distributed from central areas to tissues and exhibited higher accumulation in specific organs. The highest deposition of PK-L4-loaded SLNs with PEG was found in the lung and spine.


CONCLUSIONS
Sufficient amounts of PK-L4 were entrapped in the SLNs, and the pharmacokinetic behavior of PK-L4-loaded SLNs was established. This formulation successfully resolved the delivery problem, and the drug was localized in particular organs.
Department of Biotechnology, Yuanpei University, Hsinchu, Taiwan.
Yi-Ping
YP
Fang
Pao-Chu
PC
Wu
Yaw-Bin
YB
Huang
Cherng-Chyi
CC
Tzeng
Yeh-Long
YL
Chen
Yu-Han
YH
Hung
Ming-Jun
MJ
Tsai
Yi-Hung
YH
Tsai
D000677:Amsacrine / Q000008:administration & dosage* / Q000031:analogs & derivatives / Q000493:pharmacokinetics*; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D007275:Injections, Intravenous; D008055:Lipids / Q000737:chemistry*; D008297:Male; D008657:Metabolic Clearance Rate; D053769:Nanocapsules / Q000008:administration & dosage / Q000737:chemistry*; D009928:Organ Specificity; D011092:Polyethylene Glycols / Q000737:chemistry*; D051381:Rats; D017208:Rats, Wistar; D012995:Solubility; D014018:Tissue Distribution
D000970:Antineoplastic Agents; D008055:Lipids; D053769:Nanocapsules; D000677:Amsacrine; D011092:Polyethylene Glycols