Abstract
With the effectiveness of therapeutic agents ever decreasing and the increased incidence of multi-drug resistant pathogens, there is a clear need for administration of more potent, potentially more toxic, drugs. Alternatively, biopharmaceuticals may hold potential but require specialized protection from premature in vivo degradation. Thus, a paralleled need for specialized drug delivery systems has arisen. Although cell-mediated drug delivery is not a completely novel concept, the few applications described to date are not yet ready for in vivo application, for various reasons such as drug-induced carrier cell death, limited control over the site and timing of drug release and/or drug degradation by the host immune system. Here, we present our hypothesis for a new drug delivery system, which aims to negate these limitations. We propose transport of nanoparticle-encapsulated drugs inside autologous macrophages polarized to M1 phenotype for high mobility and treated to induce transient phagosome maturation arrest. In addition, we propose a significant shift of existing paradigms in the study of host-microbe interactions, in order to study microbial host immune evasion and dissemination patterns for their therapeutic utilization in the context of drug delivery. We describe a system in which microbial strategies may be adopted to facilitate absolute control over drug delivery, and without sacrificing the host carrier cells. We provide a comprehensive summary of the lessons we can learn from microbes in the context of drug delivery and discuss their feasibility for in vivo therapeutic application. We then describe our proposed “synthetic microbe drug delivery system” in detail. In our opinion, this multidisciplinary approach may hold the solution to effective, controlled drug delivery.
Highlights
In recent years, drug delivery has become a well-documented research niche across various disciplines in science
Salmonella induced filaments (SIFs) are required for Salmonella containing vacuole (SCV) integrity, enabling continuous fusion of host vesicles to SCV and are associated with late endosomal markers such as lysosome-associated membrane proteins (LAMP), Rab7, V-ATPase, cholesterol and lysobisphosphatidic acid (LBPA), as well as low levels of mannose-6-phosphate receptor (MPR) and cathepsin D
If the right combination of these effectors are repurposed, they can be used to develop a macrophage-based delivery system for the transport and controlled delivery of therapeutic agents packaged into a “synthetic microbe” as described here, to significant benefit of patients currently struggling with diseases at non-accessible sites or those caused by multi-drug resistant pathogens
Summary
Drug delivery has become a well-documented research niche across various disciplines in science. Approaches of drug delivery into pathogenically damaged areas or poorly vascularised cancer tissues has been largely focused on treatments incorporating nanoparticles (Zhao et al, 2011; Dreaden et al, 2012; Feng et al, 2014; Huang et al, 2015; Lv et al, 2016; Tanei et al, 2016). These nanoparticles generally serve to shield harsh/labile drugs from the host and subsequently activate or release it after reaching target tissues. With the potential exception of nanoparticle uptake into target cells via complementary receptor ligands, this approach is, still more comparable to drug saturation than with specialized drug delivery per se
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