Design Considerations for Developing Hyperbranched Polyglycerol Nanoparticles as Systemic Drug Carriers

Abstract

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.

Nontransformed and Cancer Cells Can Utilize Different Endocytic Pathways To Internalize Dendritic Nanoparticle Variants: Implications on Nanocarrier Design

“…The degrees of hydrophobicity of the unmodified HPG NPs were measured and reported before with pyrene fluorescence probe method. 16 The orders of hydrophobicity of unmodified and Alexa 488-conjugated HPG NPs remain the same. The results of these complementary methods revealed that the conjugation of the Alexa dye did not influence the order of hydrophobicity of the HPG NPs.…”

“…The syntheses and physicochemical characterization of these HPG NPs were reported previously. 16 HPG-C 10 -HPG is a nanoparticle that contains a hydrophobic core of C10 alkyl chains with a hydrophilic HPG shell. HPG-C 10 -PEG is similar to HPG-C 10 -HPG, except that the polyethylene glycol (PEG) shell was grafted onto the surface of the nanoparticle.…”

“…Moreover, we have recently reported the delivery of docetaxel using two of these HPG NPs and found that these formulations widen the therapeutic index of the drug at the cellular level, and we hypothesized that the HPG NP:drug complex interacts with cancer and normal cells differently. 14,16 To investigate how the chemical composition of HPG NPs affects cellular interaction, we labeled three HPG NP variants with Alexa 488 and followed their interaction with cancer and normal cells. In this study, we found that cancer and normal cells utilize different endocytic mechanisms to internalize these nanoparticles.…”

Thermal Conductivity and Stability of Hydrocarbon-Based Nanofluids with Palladium Nanoparticles Dispersed by Modified Hyperbranched Polyglycerol

“…HPG ( M n = 6659, M w / M n = 1.3) was prepared in our laboratory, according to the literature. 34 , 35 The hyperbranched polyglycerols were synthesized by anionic ring-opening polymerization, and the monomers in the reactions should be added very slowly to ensure low polydispersity.…”

Hyperbranched polyglycerol nanoparticles based multifunctional, nonmigrating hindered phenolic macromolecular antioxidants: Synthesis, characterization and its stabilization effect on poly(vinyl chloride)

“…Among such highly branched macromolecules, hyperbranched polyglycerol (HbPG) with average diameter in the few nanometer range (~2-20 nm) and with both chain end and pendant hydroxyl functionalities offers a variety of new derivatization processes to obtain materials with advantageous application possibilities, ranging from biomedicine to nanotechnologies and large scale commodities as well [9][10][11][12][13][14][15][16][17][18]. HbPG is a polyether polyol, which has favorable properties, namely low cytotoxicity, biocompatibility, water solubility and low viscosity [19][20][21].…”