Original Article
Optimizing particle size of docetaxel-loaded micelles for enhanced treatment of oral epidermoid carcinoma

https://doi.org/10.1016/j.nano.2016.04.012Get rights and content

Abstract

Understanding how the size of nanocarriers affects their fate in biological systems in vivo is of fundamental importance for rational design of drug delivery systems. In this study, five docetaxel (DTX)-loaded methoxy poly(ethylene glycol)-poly(lactide) micelles of different sizes (30-230 nm) were prepared. It was observed that the permeation of micelles within both the multicellular tumor spheroids and tumor xenografts in mice was dependent on the size of the micelle. In addition, the size of micelles influenced their pharmacokinetic behavior. DTX-loaded pH-sensitive micelle based on poly(ethylene glycol)-poly(lactide)-poly(β-amino ester) (DTX-pHPM) was constructed to further illustrate the effect of particle size. As expected, DTX-pHPM improved tumor penetration, uptake by tumor cells, and prolonged circulation time, consequently demonstrating the highest inhibition of in vivo tumor growth (84.4%) in oral epidermoid carcinoma. Taken together, our findings can aid in designing nano-scale drug delivery systems for cancer therapy by optimizing the particle size.

Graphical Abstract

Five micelles (30-230 nm) based on methoxy poly(ethylene glycol)-poly(lactide) copolymers and one size/charge-changing micelle based on amphiphilic poly(β-amino ester) derivates were prepared for the investigation of size effects. Through rational design of the particle size, an optimal micellar formulation of docetaxel with prolonged circulation time, improved intratumoral penetration, and enhanced cellular uptake was obtained to impede the tumor growth effectively.

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Section snippets

Materials, cell lines, and animals

Monomethoxy poly(ethylene glycol) (MPEG, Mn: 2000 and 5000), 3-amino-1-propanol, and stannous octoate (Sn(Oct)2) were purchased from Sigma (USA). D, L-Lactide was purchased from Shandong Institute of Medical Instruments (Ji'nan, China). Docetaxel was obtained from Hisun Pharmaceutical Co., Ltd. (Hangzhou, China). 1,1'-Dioctadecyl-3,3,3',3'- tetramethylindotricarbocyanine iodide (DiR), a near-infrared dye, was purchased from Biotium (Invitrogen, USA). Curcumin (CUR), acryloyl chloride, and 1,

Synthesis and characterization of copolymers

A series of MPEG-PLA copolymers were synthesized with fixed PEG blocks (5000 Da) and PLA block of varying lengths. Using the 1H NMR spectra (Figure S1), the molecular weight of PLA block for each copolymer was calculated by the integrals of the peaks corresponding to the PEG methylene protons (CH2, δ 3.7 ppm) and the PLA methyne protons (CH, δ 5.1 ppm) (Table 1). The route of synthesis of MPEG-PLA-PAE is illustrated in Figure 1. Compared with the 1H NMR spectra of MPEG-PLA, new peaks at 1.70,

Discussion

There are three major phases in nanoparticle drug delivery: systemic circulation, intratumoral penetration, and interaction with tumor cells. It is believed that particle size is a major attribute influencing the design of nanoparticulate systems. Thus, in this study, the effect of particle size on the interactions between nanoparticles and biological systems in relation to these three phases was examined to determine how particle design could be optimized for efficient cancer therapy.

During

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Conflict of interest statement: No conflict of interest is reported by the authors of this paper.

Funding sources: This work was supported by National Natural Science Funds for Excellent Young Scholar (81222047).

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