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. 2013:8:4315-26.
doi: 10.2147/IJN.S51629. Epub 2013 Nov 7.

Synthesis, characterization, and evaluation of paclitaxel loaded in six-arm star-shaped poly(lactic-co-glycolic acid)

Yongxia Chen  1 , Ziying Yang, Chao Liu, Cuiwei Wang, Shunxin Zhao, Jing Yang, Hongfan Sun, Zhengpu Zhang, Deling Kong, Cunxian Song
Affiliations

Synthesis, characterization, and evaluation of paclitaxel loaded in six-arm star-shaped poly(lactic-co-glycolic acid)

Yongxia Chen et al. Int J Nanomedicine. 2013.

Abstract

Background: Star-shaped polymers provide more terminal groups, and are promising for application in drug-delivery systems.

Methods: A new series of six-arm star-shaped poly(lactic-co-glycolic acid) (6-s-PLGA) was synthesized by ring-opening polymerization. The structure and properties of the 6-s-PLGA were characterized by carbon-13 nuclear magnetic resonance spectroscopy, infrared spectroscopy, gel permeation chromatography, and differential scanning calorimetry. Then, paclitaxel-loaded six-arm star-shaped poly(lactic-co-glycolic acid) nanoparticles (6-s-PLGA-PTX-NPs) were prepared under the conditions optimized by the orthogonal testing. High-performance liquid chromatography was used to analyze the nanoparticles' encapsulation efficiency and drug-loading capacity, dynamic light scattering was used to determine their size and size distribution, and transmission electron microscopy was used to evaluate their morphology. The release performance of the 6-s-PLGA-PTX-NPs in vitro and the cytostatic effect of 6-s-PLGA-PTX-NPs were investigated in comparison with paclitaxel-loaded linear poly(lactic-co-glycolic acid) nanoparticles (L-PLGA-PTX-NPs).

Results: The results of carbon-13 nuclear magnetic resonance spectroscopy and infrared spectroscopy suggest that the polymerization was successfully initiated by inositol and confirm the structure of 6-s-PLGA. The molecular weights of a series of 6-s-PLGAs had a ratio corresponding to the molar ratio of raw materials to initiator. Differential scanning calorimetry revealed that the 6-s-PLGA had a low glass transition temperature of 40°C-50°C. The 6-s-PLGA-PTX-NPs were monodispersed with an average diameter of 240.4±6.9 nm in water, which was further confirmed by transmission electron microscopy. The encapsulation efficiency of the 6-s-PLGA-PTX-NPs was higher than that of the L-PLGA-PTX-NPs. In terms of the in vitro release of nanoparticles, paclitaxel (PTX) was released more slowly and more steadily from 6-s-PLGA than from linear poly(lactic-co-glycolic acid). In the cytostatic study, the 6-s-PLGA-PTX-NPs and L-PLGA-PTX-NPs were found to have a similar antiproliferative effect, which indicates durable efficacy due to the slower release of the PTX when loaded in 6-s-PLGA.

Conclusion: The results suggest that 6-s-PLGA may be promising for application in PTX delivery to enhance sustained antiproliferative therapy.

Keywords: PLGA; PTX; antiproliferative therapy; drug delivery; nanoparticles; polymer.

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Figures

Figure 1
Figure 1
Schematic perspective view of (A) linear poly(lactic-co-glycolic acid) (PLGA), (B) three-arm star-shaped PLGA, (C) four-arm star-shaped PLGA, and (D) six-arm star-shaped PLGA.
Figure 2
Figure 2
(A) Synthetic route of six-arm star-shaped poly(lactic-co-glycolic acid) (6-s-PLGA). (B) Carbon-13 nuclear magnetic resonance spectra of (a) linear poly(lactic-co-glycolic acid) (L-PLGA) and (b) the synthesized 6-s-PLGA200 with peak assignment. The 6-s-PLGA200 exhibited a distinct resonance signal, “g.” In comparison with L-PLGA, peak “g” was attributed to the -CH of inositol in the 6-s-PLGA200, indicating that the 6-s-PLGA was synthesized successfully. (C) Fourier-transform infrared spectrum clearly showing the five representative peaks of 6-s-PLGA. (D) Gel permeation chromatography spectrogram of the molecular weight and molecular weight distribution of 6-s-PLGAx. The molecular weights of 6-s-PLGA50, 6-s-PLGA100, and 6-s-PLGA200 had a ratio of 1:2:4, which is basically in line with the molar ratio of the raw materials to initiator. (E) Glass transition temperature (Tg) of 6-s-PLGAx with the heating rate of 5.0°C/minute. The Tg rose as the molecular weight of the polymer increased. Abbreviations: PDI, polydispersity index; Sn(Oct)2, stannous octoate.
Figure 3
Figure 3
Cell growth of human aortic smooth-muscle cells incubated with blank paclitaxel-loaded six-arm star-shaped poly(lactic-co-glycolic acid) nanoparticles at three different polymer concentrations (0.22, 2.2, and 22.0 μg/mL). Blank nanoparticles based on linear poly(lactic-co-glycolic acid) (L-PLGA) solutions were used as controls. Notes: In nanoparticle form, there was no significant difference between the six-arm star-shaped poly(lactic-co-glycolic acid) (6-s-PLGA) and the commercially available L-PLGA, suggesting the favorable biocompatibility of 6-s-PLGA.
Figure 4
Figure 4
Effect curves of (A) polymer concentration, (B) ultrasonic time, (C) polyvinyl alcohol (PVA) concentration, and (D) water and oil phase volume ratio (W/O) on the particle size of paclitaxel-loaded six-arm star-shaped poly(lactic-co-glycolic acid) nanoparticles. Notes: A polymer concentration of 30 mg/mL, ultrasonic time of 8 minutes, PVA concentration of 1%, and W/O of 3/1 were chosen as the optimal conditions when the particle size was at a minimum.
Figure 5
Figure 5
(A) Schematic diagram of the formation of paclitaxel-loaded six-arm star-shaped poly(lactic-co-glycolic acid) nanoparticles (6-s-PLGA-PTX-NPs). (B) Transmission electron microscopy image of 6-s-PLGA-PTX-NPs. (C) Particle size and size distribution. The 6-s-PLGA-PTX-NPs obtained had an average size of 240.4±6.9 nm. (D) Zeta potential (−4.51 mV) of the 6-s-PLGA-PTX-NPs. Abbreviations: W, water; O, oil.
Figure 6
Figure 6
(A) Particle size and (B) paclitaxel loading capacity of paclitaxel-loaded six-arm star-shaped poly(lactic-co-glycolic acid) nanoparticles (6-s-PLGA-PTX-NPs) at baseline and after 1 month. Paclitaxel-loaded linear poly(lactic-co-glycolic acid) nanoparticles (L-PLGA-PTX-NPs) were tested as the control. Notes: Bars represent mean ± standard deviation (n=3). No obvious change was observed in mean particle size or drug-loading capacity of the 6-s-PLGA-PTX-NPs during storage. This indicates the prepared 6-s-PLGA-PTX-NPs had satisfactory stability in both aqueous solution and lyophilized powder form at 4°C.
Figure 7
Figure 7
In vitro release profiles of paclitaxel (PTX) from paclitaxel-loaded six-arm star-shaped poly(lactic-co-glycolic acid) nanoparticles (6-s-PLGA-PTX-NPs) and paclitaxel-loaded linear poly(lactic-co-glycolic acid) nanoparticles (L-PLGA-PTX-NPs) in 1.0 M sodium salicylate solution at 37°C. Notes: The 6-s-PLGA-PTX-NPs had a slower and more stable PTX release within 30 days than the L-PLGA-PTX-NPs, which exhibited complete and rapid PTX release in the same test period.
Figure 8
Figure 8
In vitro proliferative inhibitive effect of (A) paclitaxel-loaded six-arm star-shaped poly(lactic-co-glycolic acid) nanoparticles (6-s-PLGA-PTX-NPs) and (B) paclitaxel-loaded linear poly(lactic-co-glycolic acid) nanoparticles (L-PLGA-PTX-NPs) at four different concentrations on human aortic smooth-muscle cells. Notes: The cytostatic effect of paclitaxel (PTX) was dose dependent, and, in general, the 6-s-PLGA-PTX-NPs showed a similar antiproliferative effect to L-PLGA-PTX-NPs within 7 days. However, the 6-s-PLGA-PTX-NPs demonstrated a long-term antiproliferative effect and will require fewer administrations due to the slower release of PTX from six-arm star-shaped poly(lactic-co-glycolic acid).
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