Original Article
Investigation of hydrophobically derivatized hyperbranched polyglycerol with PEGylated shell as a nanocarrier for systemic delivery of chemotherapeutics

https://doi.org/10.1016/j.nano.2015.04.016Get rights and content

Abstract

We report the synthesis and characterization of a polymeric nanoparticle (NP) based on hyperbranched polyglycerol (HPG) containing a hydrophobic core and a hydrophilic shell, and assessed its suitability to be developed as a systemic anticancer drug carrier. HPG NP displayed low toxicity to primary cell cultures and were well-tolerated in mice after intravenous administration. When tested in mice tumor xenograft models, HPG NP accumulated significantly in the tumors with low accumulation in the liver and the spleen. In vitro studies demonstrated that HPG NP was capable of hydrophobically binding docetaxel and releasing it in a controlled manner. The HPG NP formulation of docetaxel conferred a preferential protective effect on primary non-cancerous cells while effectively killing cancer cells, indicating great potential for widening its therapeutic index. Taken together, these data indicate that HPG NP is a highly promising nanocarrier platform for systemic delivery of anticancer drugs.

From the Clinical Editor

The use of polyethylene glycol on nano-carriers as "stealth" to deliver intravenous drugs is well known. Here, the authors developed polymeric nanoparticle (NP) with hyperbranched polyglycerol (HPG) and tested its efficacy in delivering docetaxel. The results showed that this formulation could preferentially killed cancer cells with a high therapeutic index. It seems that this platform could have a great potential in cancer therapy.

Graphical Abstract

A hyperbranched polyglycerol-based nanoparticle (HPG NP) containing a hydrophobic core and a PEGylated shell was evaluated for its safety and biodistribution in tumor-bearing mice. This nanoparticle accumulated at significant level in the tumors and was well-tolerated in vitro and in vivo. The nanoparticle formulation of docetaxel (DTX) was found to confer a preferential protective effect on normal cells while killing cancer cells. The results of the study indicate that this nanoparticle is a potential carrier for systemic anticancer drug delivery.

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Section snippets

Materials and methods

All the reagents and chemicals were purchased from Sigma-Aldrich, Canada (Oakville, Ontario) and used without further purification unless mentioned. Glycidol was purified by distillation under reduced pressure before use and stored over molecular sieves at 4 °C. Octyl/decyl glycidyl ether (ODGE) was purified by distillation under reduced pressure. Tritiated methyl iodide was purchased from ARC Radiochemical (St. Louis. MO) as solution in toluene and was used directly after dilution in

Synthesis and characterization of HPG NP

HPG NP used in the present study was synthesized by the anionic ring opening polymerization of glycidol with epoxide-containing co-monomers by a two-step procedure. In the first step, a mixture of glycidol and octadecyl glycidyl ether (ODGE) was polymerized using trimethylol propane (TMP) as the initiator at 95 °C. In the second step, polymerization was continued in the same sample pot by the addition of α-epoxy-ω-methoxy polyethylene glycol (mPEG400-epoxide) to afford the HPG NP with

Discussion

Biocompatibility is a major consideration for developing drug carriers for parenteral administrations. For instance, early promises of developing dendrimers into nanocarriers were hindered by high levels of cytotoxicity27 until modifications of dendrimers were introduced to lessen their adverse effects.28 The results of our in vitro and in vivo studies suggest that HPG NP (HPG-C10-PEG) is biocompatible. It exhibited much lower cytotoxicity (IC50 of 0.6-1.2 mg/mL) when compared with G7 dendrimers

Acknowledgment

Support from Dr. Donald E. Brooks is gratefully acknowledged. The wonderful technical support from the staff at Investigation Drug Program and Animal Resources Centre at the BC Cancer Research Centre were much appreciated, and from Mr. Aarman Rahim. We also thank free.clipartof.com and cliparts.co for making the clip arts of the mouse and the syringe available for the composition of the graphical abstract.

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    The authors have no conflict of interest to disclose.

    The authors would like to acknowledge the start-up funds for MKK from the BC Cancer Agency and the University of British Columbia. This work is also partially funded by Pancreatic Cancer Canada. JNK acknowledges Michael Smith Foundation for Health Research Career Award and funding support from CIHR and NSERC.

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