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Drug Delivery

Drug Delivery - Poster Session B

Poster J6 - Development of Scalable Doxorubicin Nanoparticles with Optimized Sustained Release

Thursday, October 24, 2024
2:45 PM – 3:45 PM EST
Location: Exhibit Hall E, F & G

Introduction:  Doxorubicin (DOX) has been widely used as a chemotherapy drug for multiple cancer types, including breast, ovarian, and bladder cancer since the 1960s [1]. However, due to strong cytotoxicity and short half-life in blood circulation, its usage was quite limited. Over the past decade, nanomedicine has been intensively employed to improve its therapeutic performance. Traditional DOX nanoparticles (NPs), including silicon quantum dots, liposome, or polymeric micelles, exhibit drug releasing duration ranging from several hours to several days [2]. Despite these efforts, developing scalable, reproducible, and efficient DOX NPs with sustained release remains challenging. In this study, we have developed a NP formulation with a two-week releasing period and high potential for scaling up to industrial production.

Materials and

Methods:  Doxorubicin (DOX), tannic acid (TA), and human serum albumin (HSA) were purchased from Sigma-Aldrich Chemical Co. (St. Louis, MO). A Flash Nanocomplexation/Flash Nanoprecipitation (FNC/FNP) process was employed to encapsulate DOX into poly(ethylene glycol) and poly(lactic acid-co-glycolic acid) (PEG-b-PLGA) NPs [3]. In this process, DOX and TA solutions were pre-mixed and introduced into a confined impingement jets (CIJ) mixer along with the HSA solution. The turbulent flow within the mixer ensured uniform mixing, forming nanocomplexes mediated by hydrogen bonding. These nanocomplexes then co-precipitated with block co-polymer dissolved in various organic solvents, forming DOX-TA/HSA@PEG-PLGA NPs.

Results, Conclusions, and Discussions: Four water-miscible organic solvents (acetonitrile (ACN), dimethyl sulfoxide (DMSO), 1,4-dioxane, and 2-methoxyethanol) were used to dissolve the block copolymer, resulting in consistently encapsulated (~80%) NPs with a size distribution of 40 to 60 nm (Table 1). The most optimized formulation, NP #2 (prepared using DMSO) exhibited a releasing period of two weeks (Fig. 1A). To assess shelf stability, lyophilized NP #2 samples were stored at room temperature and reconstituted in DI water at predetermined intervals, showing less than 4% change in size over three weeks (Fig. 1B). Five batches of NP #2 were prepared under identical conditions, showing nearly complete overlap in size distribution (Fig. 1C), which validated the reproducibility of this formulation. Scalability tests expanded the batch volume from 5 mL to 150 mL, and an aliquot was taken every 30 mL during fabrication process. The size and surface charge of NP #2 were consistently maintained at 52.3 ± 5.7 nm and -16.5 ± 2.2 mV, respectively, throughout all samples (Fig. 1D).
While NPs synthesized by the FNC/FNP procedure exhibit high potential of translation to an industrial scale, the use of overnight dialysis to remove organic solvents presents a bottleneck in the translation process. To address this, tangential flow filtration (TFF) was utilized for continuous purification, effectively reducing the DMSO concentration to 2% v/v, which fits the requirements of pharmaceuticals for human use by FDA [4]. NPs purified by TFF demonstrated a size distribution similar to those purified by dialysis, with their intensity profiles overlapping well (Fig. 1E). Furthermore, NPs purified by TFF maintained a sustained release period of 2 weeks, which showed little difference with the dialysis method (Fig. 1F).
In conclusion, a DOX NP with 2-week releasing period was developed using FNC/FNP method. This system exhibits desirable properties, including high shelf stability at room temperature, ideal reproducibility, and scalability. Additionally, TFF was employed as the purification method, overcoming the scalability limitation of conventional dialysis method. These advancements pave the way for large-scale production of nanomedicines, demonstrating the potential for broader clinical applications.

Acknowledgements (Optional):  Reference:
1. Johnson-Arbor, K. and R. Dubey, Doxorubicin, in StatPearls. 2024: Treasure Island (FL).
2. Mal, A., et al., pH-responsive sustained delivery of doxorubicin using aminated and PEGylated mesoporous silica nanoparticles leads to enhanced antitumor efficacy in pre-clinical orthotopic breast cancer model. Journal of Drug Delivery Science and Technology, 2022. 77: p. 103800.
3. Li, L., et al., Quaternary nanoparticles enable sustained release of bortezomib for hepatocellular carcinoma. Hepatology, 2022. 76(6): p. 1660-1672.
4. Administration., U.S. FDA. Q3C Tables and List Rev. 4. Center for Biologics Evaluation and Research, Center for Drug Evaluation and Research. 2018.