Phytochemicals and Cancer Treatment: Cell-Derived and Biomimetic Vesicles as Promising Carriers

Abstract

The majority of anticancer agents currently used derive from natural sources: plants, frequently the ones employed in traditional medicines, are an abundant source of mono- and diterpenes, polyphenols, and alkaloids that exert antitumor activity through diverse mechanisms. Unfortunately, many of these molecules are affected by poor pharmacokinetics and limited specificity, shortcomings that may be overcome by incorporating them into nanovehicles. Cell-derived nanovesicles have recently risen to prominence, due to their biocompatibility, low immunogenicity and, above all, targeting properties. However, due to difficult scalability, the industrial production of biologically-derived vesicles and consequent application in clinics is difficult. As an efficient alternative, bioinspired vesicles deriving from the hybridization of cell-derived and artificial membranes have been conceived, revealing high flexibility and appropriate drug delivery ability. In this review, the most recent advances in the application of these vesicles to the targeted delivery of anticancer actives obtained from plants are presented, with specific focus on vehicle manufacture and characterization, and effectiveness evaluation performed through in vitro and in vivo assays. The emerging overall outlook appears promising in terms of efficient drug loading and selective targeting of tumor cells, suggesting further engrossing developments in the future.

Keywords: biomimetic nanoparticles; cancer; cell-derived vesicles; extracellular vesicles; hybrid vesicles; plant derivatives.

Figure 1

Scheme representing the production and active loading of EVs or bioinspired NPs, for the treatment of cancer-affected patients.

Figure 2

Formulation techniques for the production of bioinspired EV-like NPs.

Figure 3

Schematic representation of PTX-EXOs preparation. Inhibition of metastases growth in mouse lungs upon PTX-EXOs treatment. C57BL/6 mice were IV injected with 8FlmC-FLuc-3LL-M27 (red) cells to establish pulmonary metastases; 48 h later, the mice were treated with PTX-EXOs, or taxol, or saline, or empty sonicated exosomes as a control, and the treatment was repeated every other day, seven times in total. Representative IVIS images were taken on day 21 (A). Statistical significance of metastases levels from IVIS images in lungs of treated animals compared to control mice is shown by asterisk (* p < 0.05; ** p < 0.005) (B). At the endpoint, 21 days later, mice were sacrificed, perfused, and lung slides were examined using confocal microscopy (C). Bar: 10 μm. Reproduced with permission from [72].

Figure 4

Scheme of EM-coated PEG-PTX NPs and in vivo NIR fluorescence imaging of DiR-labeled uncoated (PDN) and EM-coated (PDNM) PEG-PTX NPs. (A) In vivo imaging of 4T1 cancer-bearing BALB/c mice receiving a single injection of PDN or PDNM, respectively. The dashed black circles indicate the tumor burden. (B) Ex vivo imaging of tumor and organs excised from 4T1 tumor-bearing mice 24 h post injection of the two fluorescent formulations. Compared to PDN, the PDNM showed higher drug distributions at the tumor site. The yellow arrows point to the tumor tissue. Reproduced from [80] under the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/ accessed on 28 March 2023).