Pharmacokinetics, distribution and anti-tumor efficacy of liposomal mitoxantrone modified with a luteinizing hormone-releasing hormone receptor-specific peptide

Abstract

Background: A previous study developed a novel luteinizing hormone-releasing hormone (LHRH) receptor-targeted liposome. The aim of this study was to further assess the pharmacokinetics, biodistribution, and anti-tumor efficacy of LHRH receptor-targeted liposomes loaded with the anticancer drug mitoxantrone (MTO).

Methods: Plasma and tissue distribution profiles of LHRH receptor-targeted MTO-loaded liposomes (LHRH-MTO-LIPs) were quantified in healthy mice or a xenograft tumor nude mouse model of MCF-7 breast cancer, and were compared with non-targeted liposomes and a free-drug solution.

Results: The LHRH-MTO-LIPs demonstrated a superior pharmacokinetic profile relative to free MTO. The first target site of accumulation is the kidney, followed by the liver, and then the tumor; maximal tumor accumulation occurs at 4 h post-administration. Moreover, the LHRH-MTO-LIPs exhibited enhanced inhibition of MCF-7 breast cancer cell growth in vivo compared with non-targeted MTO-loaded liposomes (MTO-LIPs) and free MTO.

Conclusion: The novel LHRH receptor-targeted liposome may become a viable platform for the future targeted treatment of cancer.

Keywords: gonadorelin; liposome; luteinizing hormone-releasing hormone receptor; mitoxantrone; tumor targeting.

Figure 1

Characteristics of mitoxantrone-loaded liposomes. (A) TEM image of LHRH receptor-targeted mitoxantrone loaded liposomes (LHRH-MTO-LIPs). (B) Size distribution changes of LHRH-MTO-LIPs at 2 weeks at 4°C. MTO concentration was kept at 0.05 mg/mL. (C) Cumulative release kinetics of MTO from LHRH-MTO-LIPs and MTO-LIPs determined by dialysis against PBS (pH =7.4) containing 10% (v/v) plasma. Abbreviations: TEM, transmission electron microscopy; LHRH, luteinizing hormone-releasing hormone; MTO, mitoxantrone; MTO-LIP, mitoxantrone-loaded liposome; LHRH-MTO-LIP, luteinizing hormone-releasing hormone mitoxantrone-loaded liposome; PBS, phosphate buffered saline.

Figure 2

Plasma and tumor concentrations of MTO vs time profiles and tissue biodistribution. Mice were treated with MTO, MTO-LIPs, or LHRH-MTO-LIPs via intravenous administration. At the indicated time point, MTO concentrations in the plasma (A) and tumors (B) were measured. Each data point represents n=5 and is graphed as the mean and SD. As indicated by the asterisk in (A and B), there was a significant difference between free MTO administration and administration with both liposomal formulations at the indicated time point (P<0.05). The biodistribution of MTO at 1 h post-administration and 24 h post-administration was quantified in the liver, lung, kidney, spleen, and heart of the three treatment groups (C). Each bar represents n=5 graphed as the mean and SD. Abbreviations: MTO, mitoxantrone; MTO-LIP, mitoxantrone-loaded liposome; LHRH-MTO-LIP, luteinizing hormone-releasing hormone mitoxantrone-loaded liposome.

Figure 3

In vivo therapeutic study of different MTO formulations in a mice model. (A) Relative tumor volume profiles of MCF-7 tumor-bearing nude mice following intravenous administration of various MTO formulations at a 2.5 mg/kg dose. The relative tumor volume was calculated as the ratio of tumor volume to initial tumor volume. Arrows indicate the administration day. (B) Body weight change of the BALB/c nude mice bearing MCF-7 cell xenografts after intravenous injections with MTO, MTO-LIPs, LHRH-MTO-LIPs, or saline (n=6). (C) Representative histological images (×100) from the heart and liver of tumor-bearing female BALB/c mice treated with free MTO, MTO-LIPs, or LHRH-MTO-LIPs. Abbreviations: MTO, mitoxantrone; MTO-LIP, mitoxantrone-loaded liposome; LHRH-MTO-LIPs, luteinizing hormone-releasing hormone mitoxantrone-loaded liposomes.