Design Considerations for Developing Hyperbranched Polyglycerol Nanoparticles as Systemic Drug Carriers.
PEGylation is commonly used to increase the plasma residence time of anticancer drug nanocarriers. However, PEGylation may trigger antibody production and lead to accelerated blood clearance in subsequent administrations. Moreover, the presence of PEG shells on nanocarriers may also hamper endosomal escape and decrease drug payload release. To avoid these shortcomings, we synthesized and evaluated a non-PEGylated, hyperbranched polyglycerol nanoparticle (HPG NP) with a hydrophobic core and a hydrophilic HPG shell, HPG-C10-HPG, as a candidate for systemic delivery of anticancer drug. In vitro studies with primary human cell lines revealed that HPG-C10-HPG possesses low cytotoxicity. The presence of long chain alkyl groups (C1o) in the core as the hydrophobic pocket in the NP enabled the binding and sustained release of the hydrophobic drug docetaxel. Remarkably, the docetaxel-loaded HPG-C10-HPG formulation also confers preferential protection to primary cells, when compared to cancer cells, potentially widening the therapeutic index. HPG-C10-HPG, however, accumulated at higher levels in the liver and spleen when administered intravenously in mice. Comparing the biodistribution patterns of HPG-C10-HPG, PEGylated HPG-C10-PEG, and unmodified HPG in a xenograft model reveals that the accumulation pattern of HPG-C10-HPG was attributed to insufficient shielding of the hydrophobic groups by the HPG shell. Our results revealed the influence of the nature of the hydrophilic shell and the presence of hydrophobic groups on the tumor-to-tissue accumulation specificities of these HPG NP variants. Therefore, the present study provides insights into the structural considerations of future HPG NP designs for systemic drug delivery.
Nelson K Y
NK
Wong
Ripen
R
Misri
Rajesh A
RA
Shenoi
Irina
I
Chafeeva
Jayachandran N
JN
Kizhakkedathu
Mohamed K
MK
Khan
D000818:Animals; D002460:Cell Line; D000077143:Docetaxel; D004337:Drug Carriers / Q000737:chemistry*; D065546:Drug Liberation; D005990:Glycerol / Q000138:chemical synthesis* / Q000737:chemistry*; D006801:Humans; D020128:Inhibitory Concentration 50; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D053758:Nanoparticles / Q000737:chemistry* / Q000633:toxicity; D011108:Polymers / Q000138:chemical synthesis* / Q000737:chemistry*; D043823:Taxoids / Q000494:pharmacology; D014018:Tissue Distribution / Q000187:drug effects; D018675:Toxicity Tests
D004337:Drug Carriers; D011108:Polymers; D043823:Taxoids; D000077143:Docetaxel; C043941:polyglycerol; D005990:Glycerol