2 research outputs found
Hyaluronan Polymer Length, Grafting Density, and Surface Poly(ethylene glycol) Coating Influence <i>in Vivo</i> Circulation and Tumor Targeting of Hyaluronan-Grafted Liposomes
Hyaluronan-grafted liposomes (HA-liposomes) preferentially target CD44-overexpressing tumor cells <i>in vitro via</i> receptor-mediated endocytosis. We investigated the pharmacokinetics and biodistribution of HA-liposomes with various sizes of HA (MW 5โ8, 50โ60, and 175โ350 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 (175โ350 kDa, highest ligand binding affinity) HA-liposomes displayed faster clearance compared to low MW (5โ8, 50โ60 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 <i>in vivo</i>. 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 <i>ex vivo</i> 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
Additional file 1: of NKTR-102 Efficacy versus irinotecan in a mouse model of brain metastases of breast cancer
Supplementary methods contains fine details of various protocols and assays used in this work. (PDF 91รย kb