Co-Encapsulation of Multiple Antineoplastic Agents in Liposomes by Exploring Microfluidics

Abstract

The inherent complexity of cancer proliferation and malignancy cannot be addressed by the conventional approach of relying on high doses of a single powerful anticancer agent, which is associated with poor efficacy, higher toxicity, and the development of drug resistance. Multiple drug therapy (MDT) rationally designed to target tumor heterogeneity, block alternative survival pathways, modulate the tumor microenvironment, and reduce toxicities would be a viable solution against cancer. Liposomes are the most suitable carrier for anticancer MDT due to their ability to encapsulate both hydrophilic and hydrophobic agents, biocompatibility, and controlled release properties; however, an adequate manufacturing method is important for effective co-encapsulation. Microfluidics involves the manipulation of fluids at the microscale for the controlled synthesis of liposomes with desirable properties. This work critically reviews the use of microfluidics for the synthesis of anticancer MDT liposomes. MDT success not only relies on the identification of synergistic dose combinations of the anticancer modalities but also warrants the loading of multiple therapeutic entities within liposomes in optimal ratios, the protection of the drugs by the nanocarrier during systemic circulation, and the synchronous release at the target site in the same pattern as confirmed in preliminary efficacy studies. Prospects have been identified for the bench-to-bedside translation of anticancer MDT liposomes using microfluidics.

Keywords: cancer; drug delivery; liposomes; microfluidics; multiple drug therapy.

Figure 1

Scheme of the preparation of liposomes via various techniques along with their advantages and disadvantages: (A) reverse phase evaporation method; (B) thin-film hydration technique; (C) ethanol injection method; (D) detergent removal technique; (E) sonication process; (F) supercritical fluid technique; and (G) microfluidics approach. Abbreviations: EE, encapsulation efficiency; MLV, multilamellar vesicle; SUV, small unilamellar vesicle.

Figure 2

Optical microscopy image depicting the synthesis of photothermal-responsive giant magnetic liposomes encapsulating Psi NPs, drugs (doxorubicin, 17-N-allylamino-17-demethoxygeldanamycin (17-AAG), Erlotinib), gold nanorods, and DNA nanostructure via a double emulsion (w/o/w) microfluidic device (reprinted from [118], with the permission of John Wiley and Sons Limited).

Figure 3

Schematics of the multi-hydrodynamic focusing device made of two vertically combined polydimethylsiloxane layers with a microporous stencil between the passage of the lipid inlet and tge microchannel for the fabrication of catechin- and curcumin-loaded liposomes (reprinted from [124], with permission from Elsevier).

Figure 4

Schematics of the geometry of the micromixer used for the design of copper and chlorin e6 (Cu-Ce6) liposomes with diverse sizes, charges, and surface functionalization (reprinted from [128]. Copyright (2022) American Chemical Society). Abbreviations: DOTAP, 1,2-dioleoyl-3-trimethylammonium-propane; DSPE, 1,2-distearoyl-sn-glycero-3-phosphoethanolamine; DSPC, 1,2-distearoyl-sn-glycero-3-phosphocholine; PEG, polyethylene glycol; PBS, phosphate-buffered saline.

Figure 5

Schematic representation of the preparation of an amphiphilic camptothecin prodrug (TAT-PEG-SN38) linked to polyethylene glycol (PEG) and cell-penetrating peptide (TAT) co-encapsulated with curcumin in a liposome (Lip-TAT-PEG-SN38/Curcumin) and its effect in a mice model after pulmonary administration (reprinted from [131], with permission from Elsevier).

Figure 6

Schematic image of the microfluidic membrane emulsification platform for the manufacturing of nicotinamide mononucleotide and honokiol co-loaded liposomes. (A) Graphical presentation and (B) real-life image of a microfluidic device with a membrane and liquid distributor (reprinted from [133], with permission from Elsevier).