Trends in Drug Delivery Systems for Natural Bioactive Molecules to Treat Health Disorders: The Importance of Nano-Liposomes

Abstract

Drug delivery systems are believed to increase pharmaceutical efficacy and the therapeutic index by protecting and stabilizing bioactive molecules, such as protein and peptides, against body fluids' enzymes and/or unsuitable physicochemical conditions while preserving the surrounding healthy tissues from toxicity. Liposomes are biocompatible and biodegradable and do not cause immunogenicity following intravenous or topical administration. Still, their most important characteristic is the ability to load any drug or complex molecule uncommitted to its hydrophobic or hydrophilic character. Selecting lipid components, ratios and thermo-sensitivity is critical to achieve a suitable nano-liposomal formulation. Nano-liposomal surfaces can be tailored to interact successfully with target cells, avoiding undesirable associations with plasma proteins and enhancing their half-life in the bloodstream. Macropinocytosis-dynamin-independent, cell-membrane-cholesterol-dependent processes, clathrin, and caveolae-independent mechanisms are involved in liposome internalization and trafficking within target cells to deliver the loaded drugs to modulate cell function. A successful translation from animal studies to clinical trials is still an important challenge surrounding the approval of new nano-liposomal drugs that have been the focus of investigations. Precision medicine based on the design of functionalized nano-delivery systems bearing highly specific molecules to drive therapies is a promising strategy to treat degenerative diseases.

Keywords: liposomal formulations; liposomal marketed formulations; liposome–cell interaction; nano-delivery systems; protein and peptide encapsulation.

Figure 1

Number of reports on bioactive molecules and natural products over the years, retrieved by an advanced search on the Pubmed database (https://pubmed.ncbi.nlm.nih.gov accessed on 5 July 2022) combining the terms “natural products” OR “bioactive molecules”. The number of publications contrast with FDA-approved unmodified natural drugs, which reached 43% in the 1930s. With the emergence of modern high-throughput platforms for screening and synthetic combinatorial strategies, synthetic/semi-synthetic drugs inspired by natural molecules reported throughout the years predominate over unmodified natural drugs in the market, increasing from 34% in 2010 to 50% currently.

Figure 2

Development of controlled drug delivery systems. Three distinct development phases—1st, 2nd and 3rd generations—are highlighted based on therapeutic products approved by the FDA since the 1950s, when Spansule^®, the first drug release system, was approved for clinical use. The main highlights of each phase are depicted in the central column, while the main synthetic or biological material used in the drug delivery system preparation is indicated in the left column. The advent of nanotechnological drug delivery strategies is highlighted in red during the last decade of the second development phase. Future perspectives are exhibited at the bottom panel. Created using Mind the Graph (https://mindthegraph.com accessed on 14 August 2022).

Figure 3

Timeline from 1995 to 2021 concerning representative anticancer pharmaceuticals loaded in nanoparticles approved by the American Food and Drug Administration for clinical purposes.

Figure 4

Liposomes. Panel A: Structure of liposomes. ULV—unilamellar vesicle (small ULV (SUV), large ULV (LUV) and giant ULV (GUV)); MLV—multilamellar vesicle; MVV—multivesicular vesicle. Panel B: Drug loading strategies. Panel C: Liposome surface and functionalization. All figures were drawn with BioRender accessed on 1 December 2022.

Figure 5

Liposome internalization and delivery mechanisms. The figure was created with BioRender accessed on 1 December 2022.