Enhanced docetaxel delivery using sterically stabilized RIPL peptide-conjugated nanostructured lipid carriers: In vitro and in vivo antitumor efficacy against SKOV3 ovarian cancer cells.

Abstract

Docetaxel (DTX) has poor solubility, low specificity, and severe side effects. For efficient targeting of DTX to hepsin-overexpressing SKOV3 ovarian cancer cells, PEGylated and RIPL peptide (IPLVVPLRRRRRRRRC)-conjugated nanostructured lipid carriers (PEG-RIPL-NLCs) were examined for in vitro and in vivo antitumor efficacy. DTX-loaded plain NLCs (DTX-pNLCs), RIPL-NLCs (DTX-RIPL-NLCs), and PEG-RIPL-NLCs (DTX-PEG-RIPL-NLCs) were prepared using a solvent emulsification-evaporation technique. DTX was successfully loaded with high encapsulation efficiency (>93%), and all NLCs showed homogeneous dispersion with zeta potentials varying from -17 to 15 mV. Drug release was biphasic: initial rapid release, then gradual release. In vitro cytotoxicity was time- and dose-dependent: DTX-RIPL-NLCs and DTX-PEG-RIPL-NLCs exhibited greater cytotoxicity, enhanced cell apoptosis owing to the cell cycle arrest in the G2/M phase, and increased activation of the mitochondria-related intrinsic apoptosis pathway compared to DTX-pNLCs. Pharmacokinetic experiments in male Sprague-Dawley rats revealed that DTX-PEG-RIPL-NLCs increased the mean residence time of DTX but reduced total body clearance and volume of distribution. In a SKOV3-bearing xenograft Balb/c athymic mouse model, DTX-PEG-RIPL-NLCs suppressed tumors, evidenced by tumor volume change and histopathological examination. Thus, we conclude that PEG-RIPL-NLCs have an advantage of high payload of poorly water-soluble drugs and are a good candidate for drug targeting to SKOV3-derived ovarian cancer.

• Authors: Chang Hyun Kim, Tae Hoon Kang, Byoung Deok Kim, Tae Hwa Lee, Ho Yub Yoon, Yoon Tae Goo, Yong Seok Choi, Myung Joo Kang, Young Wook Choi
• Journal: International journal of pharmaceutics (Int J Pharm) Vol. 583 Pg. 119393 (Jun 15 2020) ISSN: 1873-3476 [Electronic] Netherlands
• PMID: 32376445 (Publication Type: Comparative Study, Journal Article)
• Copyright: Copyright © 2020 Elsevier B.V. All rights reserved.

Chemical References

• Antineoplastic Agents
• Cell-Penetrating Peptides
• Drug Carriers
• Lipids
• RIPL peptide
• Docetaxel

Topics

• Animals
• Antineoplastic Agents (administration & dosage, chemistry, pharmacokinetics)
• Apoptosis (drug effects)
• Cell Line, Tumor
• Cell-Penetrating Peptides (chemistry, metabolism)
• Docetaxel (administration & dosage, chemistry, pharmacokinetics)
• Drug Carriers
• Drug Compounding
• Drug Liberation
• Female
• G2 Phase Cell Cycle Checkpoints (drug effects)
• Humans
• Injections, Intravenous
• Lipids (chemistry)
• Male
• Mice, Inbred BALB C
• Mice, Nude
• Nanoparticles
• Ovarian Neoplasms (drug therapy, metabolism, pathology)
• Rats, Sprague-Dawley
• Tumor Burden (drug effects)
• Xenograft Model Antitumor Assays