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. 2024 Jun 1:19:5071-5094.
doi: 10.2147/IJN.S457482. eCollection 2024.

Crafting Docetaxel-Loaded Albumin Nanoparticles Through a Novel Thermal-Driven Self-Assembly/Microfluidic Combination Technology: Formulation, Process Optimization, Stability, and Bioavailability

Juan Du #  1 , Li-Li Shi #  2 , Wei-Wei Jiang  3 , Xue-Ai Liu  3 , Xin-Hong Wu  3 , Xiang-Xiang Huang  3 , Ming-Wei Huo  3 , Ling-Zhi Shi  3 , Jingjian Dong  2 , Xiaohong Jiang  2 , Renyu Huang  4 , Qing-Ri Cao  3 , Wenzhou Zhang  1
Affiliations

Crafting Docetaxel-Loaded Albumin Nanoparticles Through a Novel Thermal-Driven Self-Assembly/Microfluidic Combination Technology: Formulation, Process Optimization, Stability, and Bioavailability

Juan Du et al. Int J Nanomedicine. .

Abstract

Background: The commercial docetaxel (DTX) formulation causes severe side effects due to polysorbate 80 and ethanol. Novel surfactant-free nanoparticle (NP) systems are needed to improve bioavailability and reduce side effects. However, controlling the particle size and stability of NPs and improving the batch-to-batch variation are the major challenges.

Methods: DTX-loaded bovine serum albumin nanoparticles (DTX-BSA-NPs) were prepared by a novel thermal-driven self-assembly/microfluidic technology. Single-factor analysis and orthogonal test were conducted to obtain the optimal formulation of DTX-BSA-NPs in terms of particle size, encapsulation efficiency (EE), and drug loading (DL). The effects of oil/water flow rate and pump pressure on the particle size, EE, and DL were investigated to optimize the preparation process of DTX-BSA-NPs. The drug release, physicochemical properties, stability, and pharmacokinetics of NPs were evaluated.

Results: The optimized DTX-BSA-NPs were uniform, with a particle size of 118.30 nm, EE of 89.04%, and DL of 8.27%. They showed a sustained release of 70% over 96 hours and an increased stability. There were some interactions between the drug and excipients in DTX-BSA-NPs. The half-life, mean residence time, and area under the curve (AUC) of DTX-BSA-NPs increased, but plasma clearance decreased when compared with DTX.

Conclusion: The thermal-driven self-assembly/microfluidic combination method effectively produces BSA-based NPs that improve the bioavailability and stability of DTX, offering a promising alternative to traditional formulations.

Keywords: DTX-BSA nanoparticles; in-vitro release; microfluidic technology; pharmacokinetics; thermal-driven self-assembly.

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Conflict of interest statement

The authors report no conflicts of interest in this work.

Figures

None
Graphical abstract
Figure 1
Figure 1
Flow chart of the preparation process of DTX-BSA-NPs through a microfluidic technology.
Figure 2
Figure 2
Effects of various factors on the particle size and EE of DTX-BSA-NPs. (A) the effect of mass ratio of DTX to BSA. (B) the effect of BSA concentration. (C) the effect of DTX concentration. (D) the effect of incubation temperature. (E) the effect of incubation time. (F) the effect of different buffer types. (G) the influence of preheating BSA. All data are presented as mean±SD (n = 3), with color bars indicating particle size and a line chart displaying EE.
Figure 3
Figure 3
Effects of various factors on the DL of DTX-BSA-NPs. (A) the effect of mass ratio of DTX to BSA. (B) the impact of BSA concentration. (C) the effect of DTX concentration. (D) the effect of incubation temperature. (E) the impact of incubation time. (F) the effect of different buffer types. (G) the influence of BSA preheating. All data are presented as mean±SD (n = 3).
Figure 4
Figure 4
Effects of Preparation process on DTX-BSA-NPs. (A and B) show the effect of flow rate and pump pressure on particle size and EE, with color bars indicating particle size and a line chart displaying EE. (C and D) show the effect of flow rate and pump pressure on DL. All data are presented as mean±SD (n=3).
Figure 5
Figure 5
Batch-to-batch reproducibility and freeze drying stability of DTX-BSA-NPs. (A) the particle size and zeta potential of three different batches, with color bars indicating particle size and a line chart displaying zeta potential. (B) the EE and DL of three different batches, with color bars indicating EE and a line chart displaying DL. (C) the consistency in particle size and EE of freeze-dried NPs upon reconstitution, with color bars indicating particle size and a line chart displaying EE. (D) the consistency in DL of freeze-dried NPs upon reconstitution. (E) the particle size and EE before and after freeze drying, with color bars indicating particle size and a line chart displaying EE. (F) the DL of freeze-dried NPs before and after freeze drying. (G and H) the PDI of DTX-BSA-NPs before and after freeze drying. All data are presented as mean±SD (n=3).
Figure 6
Figure 6
Appearance of freeze-dried powder and reconstituted suspension of DTX-BSA-NPs. (Left: freeze-dried powder; Right: reconstituted suspension).
Figure 7
Figure 7
TEM images of DTX-BSA-NPs. Scale bar = 200 nm.
Figure 8
Figure 8
DSC spectra of (A) DTX, (B) BSA, (C) physical mixture of DTX, BSA and sodium gluconate, and (D) DTX-BSA-NPs.
Figure 9
Figure 9
FT-IR spectra of (A) DTX, (B) BSA, (C) physical mixture of DTX, BSA and sodium gluconate, and (D) DTX-BSA-NPs.
Figure 10
Figure 10
In-vitro release profiles of DTX-BSA-NPs and DTX. All data are presented as mean±SD (n=3).
Figure 11
Figure 11
Stress test of commercial product (DTX) and DTX-BSA-NP powders. (A and B) illustrate the influence of strong light (4500±500 Lx) on pH value and content of DTX. (C and D) present the impact of high temperature (60±2°C) on pH value and content of DTX. (E and F) demonstrate the influence of high humidity (92.5±5% RH) on pH value and content of DTX. All data are presented as mean±SD (n=3).
Figure 12
Figure 12
Accelerated test of DTX and DTX-BSA-NPs. (A and B) illustrate the changes in pH value and DTX content under storage at 25°C. (C and D) present the variation of pH value and DTX content at 40°C. All data are presented as mean±SD (n=3).
Figure 13
Figure 13
Pharmacokinetic profiles of DTX concentration over time following iv injection of DTX and DTX-BSA-NPs to SD rats (n=5).
Figure 14
Figure 14
Pharmacokinetic parameters of DTX and DTX-BSA-NPs in SD rats (n=5), *p<0.05, significant difference compared with DTX group.
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