Package Delivery: Biologics as Vectors

While biologics exhibit high selectivity and superior efficacy, all of that is dependent on the ability of the agent to reach its intended target. Ensuring that biologics are able to reach their intended targets is complicated, as not only do biologic agents come in different forms with different biochemical properties and vulnerabilities, but also must reach different targets, whether they be tissues, organs, cell-surface receptors, or intracellular organelles.1 In many research and therapeutic applications, vectors are required to facilitate the delivery of biological agents to their locations of action. 

A vector is a vehicle that delivers material (a payload) from one location to another. Vectors used for the delivery of biological agents can be biological themselves, synthetic, or comprises a combination of biological and synthetic elements. For both research and therapeutic purposes, a good vector needs to be able to be able to selectively deliver its payload to the intended location. It needs to be able to circumvent or bypass physical and biological obstacles (e.g., barriers, junctions, and membranes). Perhaps most importantly, it needs to be sufficiently non-immunogenic, as a vector cannot serve its intended function if the body recognizes it as a foreign threat and eliminates it before it can reach its target.

Foe turned friend: viral vectors

Viruses are arguably the most popular vectors used in laboratories, especially for gene therapy research. Their popularity is unsurprising given how viruses endogenously reproduce by transmitting their genetic material into host cells. The type of virus serving as the vector varies depending on the payload and the target, but lentiviruses, adenoviruses, and adeno-associated viruses (AAVs) are common options.2 Viral vectors are certainly not flawless, with factors such as integration efficiency, cargo size limitations, and immunogenicity causing issues for researchers and clinicians alike.2 However, the relative ease with which a viral vector can be generated, manipulated, and mass-produced makes it a valuable tool for therapeutic purposes, for facilitating the production of biologics, and for the creation of new agents and/or models for laboratory experimentation.3

Good things come in small packages: exosomes

Exosomes are nanosized vesicles endogenously secreted by cells that have recently been found to be facilitators of communication by transferring biological payloads between cells.4 Endogenous exosome cargoes can be quite diverse, including nucleic acids, lipids, proteins, and metabolites.5 Exosomes are capable of penetrating into deep tissues and persisting in the circulation for long periods of time. Being very similar in composition to cellular membranes, they are inherently less immunogenic than viruses or artificially constructed synthetic vectors.4 All of these factors make exosomes ideal for delivering biologics. 

Researchers are also excited about the malleability of exosomes. Exosome membrane composition can be altered in vitro to add a labeling tracker molecule (e.g., luciferase, fluorophores) or to promote specific receptor-ligand interactions to confer targeting selectivity.5 The latter property is already observed endogenously, as exosomes vary in composition depending on the cell that produces them. For example, tumor cell-produced exosomes have unique properties that allow them to traffic selectively to other tumor cells, something that could be potentially harnessed for cancer therapeutics.

Natural meets artificial: nanoparticles

Similar to the work being done with exosomes, scientists are also investigating the suitability of synthetic or semi-synthetic nanoparticles as biological agent vectors. Nanoparticles offer researchers the ability to control payload release rates, and they can be broadly separated based on their affinity for water: hydrophobic particles offer superior release rate control at the cost of biological agent stability, while hydrophilic particles offer the reverse.6 Additionally, thanks to their stability, nanoparticle vectors have been used to deliver key elements of various experimental techniques (e.g., gold particles for electron microscopy, fluorophores for imaging, and dyes for photodynamic therapy).7

Better package, better agent, better result

Biological agents are highly susceptible to small changes in environmental conditions, and vectors are therefore necessary to shield them until they reach their intended targets. A variety of agents, both biological and synthetic, capable of serving as vectors have been identified. The same technologies which now enable greater customization of biologics also facilitates greater customization of the vectors that carry them, allowing researchers to continue their work in refining and optimizing vector efficiency and efficacy. 

References:
  1. N. Skalko-Basnet, “Biologics: the role of delivery systems in improved therapy,” Biologics, 8:107-114, 2014.
  2. Y. Seow and M.J. Wood, “Biological gene delivery vehicles: beyond viral vectors,” Mol Ther, 17(5):767-777, 2009.
  3. J.C. van der Loo and J.F. Wright, “Progress and challenges in viral vector manufacturing,” Hum Mol Genet, 25(R1):R42-52, 2016 
  4. X. Luan, et al., “Engineering exosomes as refined biological nanoplatforms for drug delivery,” Acta Pharmacol Sin, 38(6):754-763, 2017.
  5. J.L. Hood, “Post isolation modification of exosomes for nanomedicine applications,” Nanomedicine (Lond), 11(13):1745-1756, 2016.
  6. R.F. Pagels and R.K. Prud'homme, “Polymeric nanoparticles and microparticles for the delivery of peptides, biologics, and soluble therapeutics,” J Control Release, 219:519-535, 2015. 
  7. O. Salata, “Applications of nanoparticles in biology and medicine,” J Nanobiotechnology, 2(1):3, 2004.
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