Advancements in Betulinic Acid-Loaded Nanoformulations for Enhanced Anti-Tumor Therapy

Abstract

Betulinic acid (BA) is a natural compound obtained from plant extracts and is known for its diverse pharmacological effects, including anti-tumor, antibacterial, anti-inflammatory, antiviral, and anti-atherosclerotic properties. Its potential in anti-tumor therapy has garnered considerable attention, particularly for the treatment of breast, lung, and liver cancers. However, the clinical utility of BA is greatly hindered by its poor water solubility, low bioavailability, and off-target toxicity. To address these issues, researchers have developed various BA-loaded nanoformulations, such as nanoparticles, liposomes, micelles, and nanofibers, aiming to improve its solubility and bioavailability, prolong plasma half-life, and enhance targeting ability, thereby augmenting its anti-cancer efficacy. In preparing this review, we conducted extensive searches in well-known databases, including PubMed, Web of Science, and ScienceDirect, using keywords like "betulinic acid", "nanoparticles", "drug delivery", "tumor", and "cancer", covering the literature from 2014 to 2024. The review provides a comprehensive overview of recent advancements in the application of BA-loaded nano-delivery systems for anti-tumor therapy and offers insights into their future development prospects.

Keywords: anti-tumor; betulinic acid; bioavailability; nanoformulations; targeting.

Graphical abstract

Figure 1

Schematic illustration depicting the fabrication process of dual-targeted nanoparticles loaded with BA (BA/GGNPs). ACS Appl Bio Mater.

Figure 2

(A) Schematic diagram of the preparation process and mechanism of COS-BA/Ce6 nanoparticles, showcasing triple synergistic treatment involving chemotherapy, PDT, and immunotherapy. (B) Flowchart of COS-BA/Ce6 nanoparticles-based chemotherapy/PDT with anti-PD-L1 therapy. (C) Tumor growth curves, (D) mean tumor weights, and (E) excised tumor images of the laser-irradiated side of mice after 14 days of treatment. (F) Tumor growth curves, (G) mean tumor weights, and (H) excised tumor images on the unirradiated side of the mice. *P < 0.05, **P < 0.01, and ***P < 0.001 indicate the statistical significances among groups. Reprinted from Cheng J, Zhao H, Li B et al. Photosensitive pro-drug nanoassemblies harboring a chemotherapeutic dormancy function potentiates cancer immunotherapy. Acta Pharm Sin B. 2023;13(2):879–896.

Figure 3

(A) Schematic diagram of the assembly and mechanism of FA-coated micelles-in-liposomes encapsulating BA and CEL (F/CL@BM) for targeted accumulation at tumor sites and induction of apoptosis in tumor-associated fibroblasts and tumor cells. (B) Representative lung tissue sections stained with hematoxylin and eosin (scale bar: 50 μm). (C) Representative photographs of excised lungs, with tumor nodules circled in yellow. Reprinted from Li C, Wang Z, Zhang Y et al. Efficient sequential co-delivery nanosystem for inhibition of tumor and tumor-associated fibroblast-induced resistance and metastasis. Int J Nanomed. 2024;19:1749–1766.

Figure 4

(A) Flowchart illustrating the preparation of PX/BA-Cys-T-HA micelles. (B) Cellular uptake studies by confocal imaging of FITC-labelled PX/BA-Cys-T-HA acting on MDA-MB-231 cells after 1 and 6 h (scale bar: 50 μm). (C) Tumor morphology collected at the end of the in vivo experiment. (D) Tumor volume (mm³) plotted against time (days). ns, not significant; ****P < 0.0001 indicate the statistical significances among groups. Reprinted from Gautam S, Marwaha D, Singh N et al. Self-assembled redox-sensitive polymeric nanostructures facilitate the intracellular delivery of paclitaxel for improved breast cancer therapy. Mol Pharm. 2023;20(4):1914–1932. Copyright 2023, adapted with permission from the American Chemical Society.

Figure 5

(A) Application of BA-loaded nanoscale delivery systems across various tumor types. (B) Annual publication trends of BA-loaded nanoformulations.