Cationic folate-mediated liposomal delivery of bis-arylidene oxindole induces efficient melanoma tumor regression

Abstract

The folate receptor (FR) is a well-validated and common target for cancer due to its high over-expression in many different cancer cells. Herein, we developed a new FR-targeting ligand (FA8) by conjugating folic acid and a cationic lipid. Owing to its favorable structural property FA8 as a ligand could be accommodated at an unusually higher molar ratio for a ligand-targeted liposome. We then encapsulated a drug-like molecule, bis-arylidene oxindole (NME2), in the targeted liposome. The resulting formulation induced potent caspase-8 up-regulation even in FR-moderately expressing melanoma cells. The NME2-associated non-targeted liposome (i.e., without FA8) or pristine NME2 could not up-regulate caspase-8. Caspase-8, an important apoptotic protein involved in the extrinsic pathway of apoptosis-signalling and inhibition of acquired drug resistance, was induced in cancer cells due to the combination treatment of liposomally associated FA8 and NME2 through the activation and subsequent cleavage of RIP-1. Consistently, in a melanoma tumor model too wherein FR is moderately expressed, significant tumour regression was obtained with this liposomal combination of FA8 and NME2. In conclusion, we demonstrate the development of a new FR-targeting ligand molecule whose higher level of inclusion (>10 mol%) in the liposomal formulation altered the mode of anticancer action of the encapsulated drug, thereby indicating a new therapeutic possibility involving FR targeted cancer treatment.

<p>Slp-coated liposomes for drug delivery and biomedical applications: potential and challenges</p>

“…As a result, Slp-coated liposomes have received increasing attention in the past decade. Liposomes are nanovesicles composed of phospholipid bilayers that have various beneficial characteristics, such as good cell affinity, 7,8 targeting properties, [9][10][11] and sustained drug-release behavior. 12 Due to their favorable ability to encapsulate both hydrophobic and hydrophilic drugs, liposomes are widely used as carriers for bioactive drugs, including antineoplastic drugs, 13,14 antimicrobial drugs, 15 antiparasitic drugs, 16 hormonal drugs, 17 proteins, 18,19 and nucleic acid drugs 20,21 such as DNA [22][23][24] and siRNA.…”

A Tungsten Nitride‐Based O2 Self‐Sufficient Nanoplatform for Enhanced Photodynamic Therapy against Hypoxic Tumors

“…The PEG sequence acted as a linker and cysteine was introduced to provide ‐SH group to conjugate the peptide on the surface of WN NPs through W–S bonds . To get better tumor accumulation effect, FA‐PEG‐SH was introduced to the system to realize active tumor targeting through the recognition between FA and the overexpressed FR on tumor cell surface . Transmission electron microscope (TEM) images suggested the nanostructure of the as‐obtained FWC NPs (Figure C) and the lattice spacing was measured to be 0.207 nm under high‐resolution TEM (HRTEM), corresponding to the (200) plane of WN (Figure S2, Supporting Information).…”

“…[12] The PEG sequence acted as a linker and cysteine was introduced to provide -SH group to conjugate the peptide on the surface of WN NPs through W-S bonds. [14] Transmission electron microscope (TEM) images suggested the nanostructure of the as-obtained FWC NPs ( Figure 1C) and the lattice spacing was measured to be 0.207 nm under high-resolution TEM (HRTEM), corresponding to the (200) plane of WN ( Figure S2, Supporting Information). [14] Transmission electron microscope (TEM) images suggested the nanostructure of the as-obtained FWC NPs ( Figure 1C) and the lattice spacing was measured to be 0.207 nm under high-resolution TEM (HRTEM), corresponding to the (200) plane of WN ( Figure S2, Supporting Information).…”

<p>A versatile endosome acidity-induced sheddable gene delivery system: increased tumor targeting and enhanced transfection efficiency</p>

“…One of the most widely used small molecules is folic acid (FA). Folate receptors (FR) are over-expressed on many tumor cells surface, yet are hardly expressed on normal cells 24. FA possesses a high binding affinity for FR and the carriers conjugated with FA will be subsequently internalized into tumor cells via the receptor-mediated endocytosis 25…”