Nanovesicles for the delivery of cardiovascular drugs

Cardiovascular diseases (CVDs) are one of the top causes of death on a global scale. According to the World Health Organization (WHO), 17.9 million people die each year as a result of CVDs. With a focus on Europe, 45% of all fatalities in the “old continent”—37% in the European Union (EU) alone—are attributable to CVDs, globally accounting for 3.9 million annual deaths.2 CVD-related diagnosis and treatment expenses increase at a fast rate and are expected to continue to rise in the next decade. As an example, the EU economic burden is estimated to be around 111 billion Euros for the direct costs of CVD treatments annually, with a 210 billion Euro yearly price tag for overall management of CVDs. This impressive economic load is substantially related to an increase in CVD-associated risk factors, which include, among others, obesity, diabetes, and population aging. Although the application of nanomedicine (NM) in the diagnosis and treatment of CVDs is substantially younger than its oncological counterpart, the rapid pace at which it progresses is testified by the number of laboratory-scale results reported, for example, on PubMed (1853 hits returned for the combined cardiovascular1nanomedicine search performed on May 25, 2021—1111 hits only in the last 5 years). From a historical perspective, the majority of the early CVD-directed nanosystems were produced with the aim to improve bioavailability, stability, and safety of medications that were already on the market. Likely, the first successful example in this respect is represented by the proof-ofprinciple study in which lipid-based nanoparticles (NPs) were engineered to revive the clinical potential of the abandoned CVD-targeting compound wortmannin, a potent inhibitor of phosphatidylinositol 30kinase-related kinases that failed clinical translation due solubility and other drug-delivery challenges.4 According to the design, these NPs had a lipid-polymer surface and a hydrophobic polymeric core in which the hydrophobic drug was incapsulated. A lipid monolayer (lecithin and PEGylated lipids [1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-amino(polyethylene glycol) (DSPE-PEG)]) was incorporated to stabilizes the NPs, while their surface was decorated with PEG to impart a stealth effect and resists serum protein adsorption and/or opsonization. In combination with drug solubility enhancement, CVD NMs are also expected to (1) protect their therapeutic cargo from systemic degradation, exert reduced toxicity and immunogenicity, be characterized by improved pharmacokinetic/pharmacodynamic profiles and halflife, and be endowed with higher bioavailability and more targeted biodistribution. Notwithstanding the intense research efforts, several technical, ethical and regulatory issues still pose major hurdles along the translational pathway of CVD NMs. This, in turn, accounts for the low number (12) of CVD NMs currently listed in ongoing clinical trials to date and the fact that no NM has been approved for CVD diagnostic/therapeutic purposes both by the United States Food and Drug Administration (FDA) and the European Medicine Agency so far. Among the plethora of NPs designed and produced as NM components, nanovesicles (NVs)—generally defined as self-assembled structures formed by single or multiple concentric bilayers that surround an aqueous core—are widely used in biomedical applications including CVDs.NVs can be both of natural (e.g., exosomes) and synthetic origin (e.g., liposomes), with dimensions ranging from the nanoscale (10^-9 m) to the microscale (10^-6 m). Liposomes, mainly consisting in closed phospholipid bilayers resembling cell membranes in composition, likely are the most popular NVs. Both the chemical and structural features of liposomes largely contributed to their adoption as NVs for drug delivery in many pathologies, including CVDs. Traditional liposomes have been subjected to substantial modifications over the years to improve those physicochemical and biological characteristics deemed critical for drug delivery and diagnostic purposes. Long-circulating (aka stealth), surface-modified, ligand-targeted, and stimuli-responsive liposomes are just a few of the outcomes of these NV modifications. It is important to observe at this point that changes in conventional liposome compositions (such as those briefly outlined earlier) have initiated a process of NV renaming. As a consequence, a Babel of terms—some rather fancy or almost exotic like, for instance, cryptosomes, DQasomes, escheriosomes, niosomes, transfersomes, and many more—began to appear in the relevant scientific literature. As a result, there is an ongoing debate about whether NVs with the suffix “some” in their name can still be considered modified liposomes or must be intended as entirely new entities, and the interested reader is referred to the excellent paper by Apolinario and coworkers for an in-depth view on this subject. According to the same authors, despite the variety of “somes” available, the few approved NVs for clinical use are still referred to as liposomes, and the adoption of this term is reinforced in the relevant final guideline document released by FDA in 2018. From the perspective of natural NVs, exosomes are NVs that have currently received the highest interest, particularly in cancer therapeutics. Exosomes are endosomal-derived extracellular vesicles (ECVs) typically 30 150 nm in diameter, and such dimensions make them the smallest among all ECVs . Delimited by a lipidic bilayer, these NVs are released into the extracellular environment along with their complex cargo derived from the original cell, including signaling molecules, proteins, lipids, and diverse forms of nucleic acids. ECVs populate different body fluids and, due to their ability to carry, transform and exchange their composite molecular load, they contribute to those cell communication mechanisms underlying cellular integrity. Some of the ECV properties like their biocompatibility, modulable targeting efficiency, and high stability render this type of natural NVs remarkable drug delivery vehicles in various diseases, including CVDs. Thus, in this chapter, we focus on liposomes and ECVs as a particular set of NV-based nanodelivery systems (NDSs) in CVDs and will report on some of the most interesting advancements in CVD NV-based therapeutics. These findings will undoubtedly catalyze the efforts of scientists active in this fascinating yet highly challenging field in the near future.