Delivery of cancer therapies by synthetic and bio-inspired nanovectors

Abstract

Background: As a complement to the clinical development of new anticancer molecules, innovations in therapeutic vectorization aim at solving issues related to tumor specificity and associated toxicities. Nanomedicine is a rapidly evolving field that offers various solutions to increase clinical efficacy and safety. MAIN: Here are presented the recent advances for different types of nanovectors of chemical and biological nature, to identify the best suited for translational research projects. These nanovectors include different types of chemically engineered nanoparticles that now come in many different flavors of 'smart' drug delivery systems. Alternatives with enhanced biocompatibility and a better adaptability to new types of therapeutic molecules are the cell-derived extracellular vesicles and micro-organism-derived oncolytic viruses, virus-like particles and bacterial minicells. In the first part of the review, we describe their main physical, chemical and biological properties and their potential for personalized modifications. The second part focuses on presenting the recent literature on the use of the different families of nanovectors to deliver anticancer molecules for chemotherapy, radiotherapy, nucleic acid-based therapy, modulation of the tumor microenvironment and immunotherapy.

Conclusion: This review will help the readers to better appreciate the complexity of available nanovectors and to identify the most fitting "type" for efficient and specific delivery of diverse anticancer therapies.

Keywords: Cancer therapy; Drug delivery; Nanomedicine; Nanoparticle; Targeting; Vectorization; Vesicle; Virus.

Fig. 1

Advantages of vectorization for delivering cancer therapies. The clinical efficacy of therapeutic molecules (e.g. chemotherapeutic drugs, radionuclides, nucleic acids, antibodies) relies on efficient tumor delivery and limited off-targeting. Nanovectors of different natures (e.g. nanoparticles, extracellular vesicles, viruses) can improve the transport of these molecules in the bloodstream by increasing their solubility, half-life and bioavailability, and by helping the crossing of biological barriers. Tumor delivery is also enhanced by improved targeting of the tumor microenvironment, leading to the accumulation of the therapeutic molecules in the tumors and thus potentiating the use of combination therapies

Fig. 2

Chemically engineered nanoparticles for cancer therapy. This class of nanovectors is commonly divided between inorganic and organic nanoparticles. Inorganic nanoparticles (e.g. metallic, silica, carbon, quantum dots) are characterized by a high stability, a low biodegradability and intrinsic electronical and optical properties suitable for cancer imaging and theranostics. Because of their solid core, therapeutic molecules are generally conjugated on their surface and may be exposed to rapid degradation in vivo. Organic nanoparticles (e.g. lipid-based, macromolecular assemblies) exhibit a lower stability but a good biocompatibility and multiple possibilities of drug functionalization on their surface or their inner space. Hybrid nanoparticles combine the advantages of both inorganic and organic families to improve the biocompatibility and the stability of the nanovector

Fig. 3

Biological and bio-inspired nanovectors for cancer therapy. These nanovectors have been derived from different types of organisms and exhibit high biocompatibility and extensive engineering possibilities. Extracellular vesicles derive from eukaryotic cell membranes and naturally transport different types of biomolecules (e.g. proteins, RNA). Bacterial minicells are achromosomal 400-nanometer vesicles that can be generated by genetic engineering of bacteria and have been recently used to vectorize various types of therapeutic molecules. Virus-like particles are basically viruses (e.g. bacteriophages, plant viruses, eukaryotic viruses) stripped of their replicative capacity; they exist as naked or enveloped capsids and sometimes require a non-replicative template genome for their assembly. On the contrary, oncolytic viruses are tumor-specific, live-replicating viruses with intrinsic cytotoxic and immunoactivating properties; they can equally be naked or enveloped and may be modified by genetic engineering to transport therapeutic transgenes that will be expressed exclusively by infected malignant cells

Fig. 4

Biogenesis of biological nanovectors. Biological nanovectors are either derived from prokaryotic (bacterial minicells) or eukaryotic (extracellular vesicles) cells, or from viruses (oncolytic viruses and virus-like particles). Bacterial minicells are achromosomal vesicles obtained upon genetic engineering (deletion of the Min operon) from ectopic septation of Gram-positive or Gram-negative bacteria. Extracellular vesicles are produced by all eukaryotic cells by outward budding of the plasma membrane (microvesicles) or through inward budding and exocytosis (exosomes). Regarding viruses, whereas live-attenuated oncolytic viruses carry a complete genome and thus retain a replicative capacity specific for transformed cells, virus-like-particles are only constituted of structural proteins and are consequently not competent for replication

Fig. 5

From the blood to the tumor cell: the difficult journey of nanovectors. Systemically injected nanovectors face several biological barriers to reach the tumor microenvironment and exert their therapeutic effect in malignant cells. First, filtering organs such as the liver (for nanovectors > 5 nm) or the kidneys (for nanovectors < 5 nm) eliminate an important fraction of the injected nanovectors. Nanovectors then extravasate from the bloodstream to the tumor either because of an increased vascular permeability (Enhanced Permeability and Retention effect) or by active transcytosis through endothelial cells. The nanovectors have to overcome the interstitial pressure and to diffuse in the extracellular matrix to reach tumor cells. This can be partially improved by active targeting strategies through nanovector engineering. Once reaching the cancer cells, nanovectors can be internalized by several mechanisms (e.g. passive or virus-mediated fusion, endocytosis, macropinocytosis) depending on their origin, size, composition and functionalization. The final difficulty consists in delivering the therapeutic cargo in the appropriate cellular compartment – generally the cytoplasm – to achieve optimal therapeutic efficacy. This usually requires further vector engineering (e.g. endosomal escape domains, pH-sensitive moieties), in particular for non-biological nanoparticles.EVs: Extracellular Vesicles; VLPs: Virus-Like Particles; OVs: Oncolytic Viruses