Synergistic dual-modified liposome improves targeting and therapeutic efficacy of bone metastasis from breast cancer

Abstract

Breast cancer frequently metastasizes to bone, where it leads to poor clinical prognosis. Due to the peculiarity of the bone microstructure, the uptake of drugs often happens at non-targeted sites, which produces a similar cytotoxicity in both cancerous and healthy cells. In this study, a rational strategy was implemented to take advantage of a combination of both an octapeptide with eight repeating sequences of aspartate (Asp) and folate to create a more selective and efficient drug delivery system to target cancer cells in bone tissue. Asp and folate were conjugated to the distal ends of DSPE-PEG-maleimide and DSPE-PEG-amine to create DSPE-PEG-Asp and DSPE-PEG-Folate, respectively, which were incorporated onto the surface of a doxorubicin (DOX)-loaded liposomes (A/F-LS). Asp, similar to the hydroxyapatite-binding domains of osteopontin and osteocalcin, has been used as bone-targeting moieties for exclusive delivery of drugs to bone. The folate moiety binds selectively to folate receptor-positive tumors. The dual-targeting effects were evaluated by both in vitro and in vivo experiments. By taking advantages of dual-targeting drug delivery, the dual-modified liposomal drug system could relieve pain and improve survival. Inspired by its enhanced therapeutic efficacy and low toxicity, DOX-loaded A/F-LS could serve as an effective drug system for targeted therapy of bone metastases.

Folate receptor targeting of radiolabeled liposomes reduces intratumoral liposome accumulation in human KB carcinoma xenografts

“…Directly targeting specific cancer cell receptors, including FRs, has proven successful in numerous in vitro studies. [39][40][41][42] Varying therapeutic effects of FR-targeting in tumor models has been observed in in vivo studies, ranging from promising to discouraging results 4,6,14,15,43,44 However, other in vivo studies has also, in agreement with the current study, targeted FR with liposomes with poor tumor accumulation compared to controls. 9,12,45 Although results by previous studies are somewhat contradicting, it may be partly explained by differences in tumor models, formulations, and other experimental details and, as previously stated, be partly explained by differences in cellular uptake.…”

Copper Complexes as Anticancer Agents Targeting Topoisomerases I and II

“…Finally, to overcome toxicity to normal cells, Top drugs could be attached to vehicles. Top2 inhibitors delivery has been optimized using liposomes [ 232 ], micelles [ 233 ], or functionalized nanoparticles [ 234 ] ( Figure 5 B).…”

Anthracyclines as Topoisomerase II Poisons: From Early Studies to New Perspectives

“…Ke et al [ 104 ] incorporated into the surface of doxorubicin loaded liposomes, eight repeated sequences of aspartate (Asp8) and folate, obtaining a dual-targeting liposomal system in which Asp8 target preferentially the resorption surface of bones and folate target the tumor cells. They nicely demonstrated by in vivo distribution imaging and binding assay, that the system has a strong bone targeting effect and high cytotoxicity, associated with a prolonged blood circulation time which favored drug accumulation in the tumor.…”