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

• Published in: International journal of pharmaceutics Vol. 583; p. 119393
• Main Authors: Kim, Chang Hyun, Kang, Tae Hoon, Kim, Byoung Deok, Lee, Tae Hwa, Yoon, Ho Yub, Goo, Yoon Tae, Choi, Yong Seok, Kang, Myung Joo, Choi, Young Wook
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 15.06.2020
• Subjects: Animals; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacokinetics; Antitumor efficacy; Apoptosis - drug effects; Cell Line, Tumor; Cell-Penetrating Peptides - chemistry; Cell-Penetrating Peptides - metabolism; Docetaxel; Docetaxel - administration & dosage; Docetaxel - chemistry; Docetaxel - 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; Nanostructured lipid carrier; Ovarian Neoplasms - drug therapy; Ovarian Neoplasms - metabolism; Ovarian Neoplasms - pathology; PEGylation; Rats, Sprague-Dawley; RIPL peptide; Targeting; Tumor Burden - drug effects; Xenograft Model Antitumor Assays; PEGylation; Nanostructured lipid carrier; Targeting; Antitumor efficacy; Docetaxel; RIPL peptide
• ISSN: 0378-5173; 1873-3476
• DOI: 10.1016/j.ijpharm.2020.119393

[Display omitted] 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.