RIPL peptide-conjugated nanostructured lipid carriers for enhanced intracellular drug delivery to hepsin-expressing cancer cells.

Abstract

BACKGROUND:

To facilitate selective and enhanced drug delivery to hepsin (Hpn)-expressing cancer cells, RIPL peptide (IPLVVPLRRRRRRRRC, 16-mer)-conjugated nanostructured lipid carriers (RIPL-NLCs) were developed.

METHODS:

NLCs were prepared using a solvent emulsification-evaporation method and the RIPL peptide was conjugated to the maleimide-derivatized NLCs via the thiol-maleimide reaction. Employing a fluorescent probe (DiI), in vitro target-selective intracellular uptake behaviors were observed using fluorescence microscopy and flow cytometry. Separately, docetaxel (DTX) was encapsulated by pre-loading technique, then cytotoxicity and drug release were evaluated. In vivo antitumor efficacy was investigated in BALB/c nude mice with SKOV3 cell tumors after intratumoral injections of different DTX formulations at a dose equivalent to 10 mg/kg DTX.

RESULTS:

RIPL-NLCs showed positively charged nanodispersion, whereas NLCs were negatively charged. DTX was successfully encapsulated with an encapsulation efficiency and drug loading capacity of 95-98% and 44-46 µg/mg, respectively. DTX release was diffusion-controlled, revealing the best fit to the Higuchi equation. Cellular uptake of DiI-loaded RIPL-NLCs was 8.3- and 6.2-fold higher than that of DiI-loaded NLCs, in Hpn(+) SKOV3 and LNCaP cells, respectively. The translocation of RIPL-NLCs into SKOV3 cells was time-dependent with internalization within 1 h and distribution throughout the cytoplasm after 2 h. DTX-loaded RIPL-NLCs (DTX-RIPL-NLCs) revealed dose-dependent in vitro cytotoxicity, while drug-free formulations were non-cytotoxic. In SKOV3-bearing xenograft mouse model, DTX-RIPL-NLCs significantly inhibited tumor growth: the inhibition ratios of the DTX solution-treated and DTX-RIPL-NLC-treated groups were 61.4% and 91.2%, respectively, compared to those of the saline-treated group (control).

CONCLUSION:

RIPL-NLCs are good candidates for Hpn-selective drug targeting with a high loading capacity of hydrophobic drug molecules.

• Authors: Sang Gon Lee, Chang Hyun Kim, Si Woo Sung, Eun Seok Lee, Min Su Goh, Ho Yub Yoon, Myung Joo Kang, Sangkil Lee, Young Wook Choi
• Journal: International journal of nanomedicine (Int J Nanomedicine) Vol. 13 Pg. 3263-3278 ( 2018) ISSN: 1178-2013 [Electronic] New Zealand
• PMID: 29910614 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents
• Drug Carriers
• Lipids
• Maleimides
• Peptides
• Taxoids
• Docetaxel
• maleimide
• Serine Endopeptidases
• hepsin

Topics

• Animals
• Antineoplastic Agents (administration & dosage, pharmacokinetics)
• Cell Line, Tumor
• Docetaxel
• Drug Carriers (administration & dosage, chemistry)
• Drug Delivery Systems (methods)
• Drug Liberation
• Female
• Humans
• Hydrophobic and Hydrophilic Interactions
• Lipids (chemistry)
• Maleimides (chemistry)
• Mice, Inbred BALB C
• Mice, Nude
• Nanostructures (chemistry)
• Particle Size
• Peptides (administration & dosage, chemistry)
• Serine Endopeptidases (metabolism)
• Taxoids (administration & dosage)
• Xenograft Model Antitumor Assays