DOPA-based paclitaxel-loaded liposomes with modifications of transferrin and alendronate for bone and myeloma targeting

Abstract

Treatment for multiple myeloma (MM) with a combined strategy of bone and tumor targeting remains a crucial technical challenge due to the incorporation of various functional components into one single system. Here, we developed dioleoyl phosphatidic acid (DOPA)-based paclitaxel (PTX)-loaded liposomes with modifications of alendronate and transferrin (Ald-/Tf-modified PTX-L), which were capable of bone affinity mediated by phosphate groups in DOPA and alendronate, and tumor targeting offered by transferrin. Ald-/Tf-modified PTX-L had clear and well-defined spherical shape with an intermediated size of 118.8 ± 4.8 nm, a highly negative surface charge of À46.9 ± 6.8 mV and a drug entrapment efficiency (DEE) of approximately 80%. When the pH was changed from pH 7.4 to pH 6.5, the accumulative release of PTX from Ald-/Tf-modified PTX-L significantly increased from 26.7 ± 3.7% to 41.7 ± 4.9%. Importantly, liposomes based on DOPA displayed an obviously stronger affinity with hydroxyapatite (HAp) than 1,2-distearoyl-sn-glycero-3-phosphoethanolamine (DSPE)-based liposomes. Compared to PTX-L, Ald-/Tf-modified PTX-L exhibited obvious improvement of cytotoxicity (IC 50 ¼ 1.25 ± 0.09 mg/mL), significant enhancement on PTX intracellular accumulation (16.58 ± 0.62 mg/mg) and notable promotion to apoptosis induction (45.21 ± 3.10%) toward myeloma (MM1s) cells. In this study of antitumor efficacy, Ald-/Tf-modified PTX-L with bone-specific targeting showed a significant effect on extending the median survival time (48 days) and terminal survival time (458 days) against the MM1S-injected nude mice among all formulations. The results suggested that Ald-/Tf-modified PTX-L had potential as an efficient anticancer drug delivery system for MM therapy.

Targeted Approaches to Inhibit Sialylation of Multiple Myeloma in the Bone Marrow Microenvironment

“…Kiziltepe et al have shown that delivering doxorubicin using a lipid-PEG block polymer nano-formulation tagged by the VLA-4 antigen was significantly more cytotoxic to MM cells compared to the free drug (Kiziltepe et al, 2012). Using an alternative approach, Chang et al developed dioleoyl phosphatidic acid (DOPA)-based paclitaxel (PTX)-loaded liposomes with modifications of alendronate and transferrin, which were able to target the bone microenvironment (Chang et al, 2016). Targeting the CD38 receptor in MM represents an additional attractive approach as CD38 is highly expressed on malignant plasma cells (De La Puente et al, 2018).…”

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

“…Thus, various targeted strategies have been applied in the field of nanocarriers to target metastatic sites in the bone. Among these strategies, an active targeted DDS is one of the most promising strategies (Chang et al., 2016 ). Hydroxyapatite is a unique mineral present in bone, which makes it an attractive target to develop bone-targeting DDS for bone-related pathologies (Jiang et al., 2012 ).…”

New Progress in Improving the Delivery Methods of Bisphosphonates in the Treatment of Bone Tumors

“…Chang et al 64 developed paclitaxel-, alendronate- and transferrin-modified liposomes (ALN-/Tf-modified paclitaxel-L) based entirely on dioleoyl phosphatidic acid (DOPA), which mediates bone affinity and tumor targeting provided by transferrin by means of DOPA and the phosphate group in alendronate. The drug delivery system has a potential bone affinity because of the substantial divalent phosphate groups exposed to the surface of liposomes containing DOPA and alendronate and enhances the uptake of MM1S cells by modifying transferrin.…”