Endothelial Selectin-targeted Nanoparticles for Enhancing Drug Delivery to Solid Tumors
Abstract
The majority of current nanoparticle drug carriers depend on hypervasculature and poor lymphatic drainage, so called the enhanced permeability and retention (EPR) effect, for selective delivery of chemotherapy to solid tumors. However, their effectiveness varies with the extent of the EPR effect. We hypothesize that the vascular endothelium interferes with the access to underlying tumors and aim to overcome the barrier by engineering nanoparticles (NPs) that address peritumoral endothelium in a similar manner as circulating leukocytes do inflamed tissues. To achieve this goal, a quinic acid (QA) derivative, a synthetic mimic of sialyl Lewis x (sLex), was conjugated on the surface of poly(lactic-co-glycolic acid) (PLGA) NPs to promote their interaction with selectin-expressing peritumoral endothelium. The QA-decorated NPs (QA-NP) interacted with human umbilical vein endothelial cells (HUVECs) activated by tumor necrosis factor-alpha (TNF-α), thereby expressing E- and P-selectins. The interaction helped QA-NP to translocate across the confluent HUVECs layer by inducing transient increase in endothelial permeability. QA-NP reached tumors with selectin upregulation, due to either local irradiation or a paracrine effect of cancer cells, showing greater tumor accumulation and paclitaxel (PTX) delivery as compared to polyethylene glycol-decorated NPs (PEG-NP). PTX-loaded QA-NP showed greater anti-cancer efficacy than Taxol, a commercial benchmark PTX formulation, or PTX-loaded PEG-NP at the equivalent PTX dose, in two different animal models and three dosing regimens. Repeated dosing of PTX-loaded QA-NP in the first two weeks resulted in complete tumor remission in 40-60% of MDA-MB-231 tumor-bearing mice, while those receiving all other control treatments succumbed to death. In addition to the selectin-mediated extravasation, the superior anti-cancer efficacy of QA-NP is attributed in part to the lack of antibody formation, which leads to the accelerated clearance of the subsequent doses. Our results support that QA-NP can exploit the interaction with selectin-expressing peritumoral endothelium and deliver anti-cancer drugs to tumors to a greater extent than the level currently possible with the EPR effect.
Degree
Ph.D.
Advisors
Yeo, Purdue University.
Subject Area
Nanotechnology|Pharmaceutical sciences|Biomedical engineering
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