Hyaluronan-grafted liposomes (HA-liposomes) preferentially target CD44-overexpressing tumor cells in vitro via receptor-mediated endocytosis. We investigated the pharmacokinetics and biodistribution of HA-liposomes with various sizes of HA (MW 5–8, 50–60, and 175–350 kDa) in mice. Incorporation of negatively charged HA on the liposome surface compromised its blood circulation time, which led to decreased tumor accumulation in CD44+ human breast cancer MDA-MB-231 xenografts compared to PEGylated liposomes (PEG-5000). Clearance of HA-liposomes was HA polymer length-dependent; high MW (175–350 kDa, highest ligand binding affinity) HA-liposomes displayed faster clearance compared to low MW (5–8, 50–60 kDa) HA-liposomes or PEGylated liposomes. Surface HA ligand density can also affect clearance of HA-liposomes. Thus, HA is not an effective stealth coating material. When dual coating of PEG and HA was used, the PEG-HA-liposomes displayed similar blood circulation time and tumor accumulation to that of the PEGylated liposomes; however, the PEG-HA-liposomes displayed better cellular internalization capability in vivo. Tumor histology showed that PEG-HA-liposomes had a more direct association with CD44+ cancer cells, while PEGylated liposomes located predominantly in the tumor periphery, with less association with CD44+ cells. Flow cytometry analysis of ex vivo tumor cells showed that PEG-HA-liposomes had significantly higher tumor cell internalization compared to PEGylated liposomes. This study demonstrates that a long blood circulation time is critical for active tumor targeting. Furthermore, the use of the tumor-targeting ligand HA does not increase total tumor accumulation of actively targeted liposomes in solid tumors; however, it can enhance intracellular delivery.
BackgroundBrain metastases are an increasing problem in women with invasive breast cancer. Strategies designed to treat brain metastases of breast cancer, particularly chemotherapeutics such as irinotecan, demonstrate limited efficacy. Conventional irinotecan distributes poorly to brain metastases; therefore, NKTR-102, a PEGylated irinotecan conjugate should enhance irinotecan and its active metabolite SN38 exposure in brain metastases leading to brain tumor cytotoxicity.MethodsFemale nude mice were intracranially or intracardially implanted with human brain seeking breast cancer cells (MDA-MB-231Br) and dosed with irinotecan or NKTR-102 to determine plasma and tumor pharmacokinetics of irinotecan and SN38. Tumor burden and survival were evaluated in mice treated with vehicle, irinotecan (50 mg/kg), or NKTR-102 low and high doses (10 mg/kg, 50 mg/kg respectively).ResultsNKTR-102 penetrates the blood-tumor barrier and distributes to brain metastases. NKTR-102 increased and prolonged SN38 exposure (>20 ng/g for 168 h) versus conventional irinotecan (>1 ng/g for 4 h). Treatment with NKTR-102 extended survival time (from 35 days to 74 days) and increased overall survival for NKTR-102 low dose (30 % mice) and NKTR-102 high dose (50 % mice). Tumor burden decreased (37 % with 10 mg/kg NKTR-102 and 96 % with 50 mg/kg) and lesion sizes decreased (33 % with 10 mg/kg NKTR-102 and 83 % with 50 mg/kg NKTR-102) compared to conventional irinotecan treated animals.ConclusionsElevated and prolonged tumor SN38 exposure after NKTR-102 administration appears responsible for increased survival in this model of breast cancer brain metastasis. Further, SN38 concentrations observed in this study are clinically achieved with 145 mg/m2 NKTR-102, such as those used in the BEACON trial, underlining translational relevance of these results.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-015-1672-4) contains supplementary material, which is available to authorized users.
Pulmonary arterial hypertension (PAH) affects more women than men, although affected females tend to survive longer than affected males. This sex-disparity in PAH is postulated to stem from the diverse roles of sex hormones in disease etiology. In animal models, estrogens appear to be implicated not only in pathologic remodeling of pulmonary arteries, but also in protection against right ventricular (RV) hypertrophy. In contrast, the male sex hormone testosterone is associated with reduced survival in male animals, where it is associated with increased RV mass, volume, and fibrosis. However, it also has a vasodilatory effect on pulmonary arteries. Further, patients of both sexes show varying degrees of response to current therapies for PAH. As such, there are many gaps and contradictions regarding PAH development, progression, and therapeutic interventions in male versus female patients. Many of these questions remain unanswered, which may be due in part to lack of effective experimental models that can consistently reproduce PAH pulmonary microenvironments in their sex-specific forms. This review article summarizes the roles of estrogens and related sex hormones, immunological and genetical differences, and the benefits and limitations of existing experimental tools to fill in gaps in our understanding of the sex-based variation in PAH development and progression. Finally, we highlight the potential of a new tissue-chip-based model mimicking PAH-afflicted male and female pulmonary arteries to study the sex-based differences in PAH and to develop personalized therapies based on patient sex and responsiveness to existing and new drugs.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.