Overcoming Physiological Challenges in LBP Delivery

Overcoming physiological challenges in the delivery of live biotherapeutic products (LBPs) is critical to ensure their effectiveness. This includes using pharmaceutical formulations and genetic engineering, as well as combinations of both. These strategies are important to modulate LBP interactions with physiological surfaces, surpass physiological obstacles, and address biocontainment issues relevant to LBP delivery.

Pharmaceutical Formulation strategies

The use of pharmaceutical formulations plays a significant role in regulating interactions between a therapeutic substance and the physiological environment it encounters. These formulations may be leveraged for LBPs to control their chemical challenges, interact with physiological tissues, and pinpoint specific areas for competitive or therapeutic benefits. In certain instances, probiotics have been coated using biocompatible lipids that were self-assembled with a brief vortex process. This reportedly improved the probiotics' resistance to various elements including enzymes, extreme pH levels, antibiotics, and ethanol. Increased resistance and improved therapeutic efficacy were subsequently observed in mouse models. Some LBP formulations were designed to mimic natural gut symbionts' abilities and functions. For example, biofilm formation was triggered in Bacillus subtilis creating a defense mechanism that improved resilience to gut enzymes and low pH and enhanced intestinal colonization.

Fig.1 Formulation and genetic engineering strategies to improve LBP delivery (Heavey, 2021)

Genetic engineering strategies

Exploring genetic engineering strategies is another essential approach to improve LBP delivery by overcoming physiological hurdles. These strategies allow for site-specific targeting, increased endurance, and persistence in the gut, and controlled drug release. Escherichia coli Nissle (EcN) was manipulated genetically to form living hydrogels through curli fiber secretion, a feature that enhanced the LBP's endurance and promoted biofilm formation. This approach significantly reduced LBP clearance due to various factors like mucosal turnover and space competition in peristalsis. Additionally, genetic engineering can reprogram LBPs to detect and respond to the host's dynamic internal environment. An example of this is the genetic modification of lactic acid bacteria to release antimicrobial substances in response to the presence of quorum-sensing molecules from Pseudomonas aeruginosa.

Pharmaceutical formulations to deliver genetically engineered LBPs

Strategies combining both pharmaceutical formulations and genetic engineering techniques to enhance LBPs' delivery have started making appearances. Some research has employed bacterial cellulose's material properties and EcN's genetic tractability to generate hybrid living capsules featuring both strains in one delivery system. Also, the encapsulation of genetically engineered E. coli in beads composed of crosslinked sodium-alginate containing polyacrylamide on the exterior created a resilient shell-like structure that imparted biocontainment and maintained genetically engineered functions. The biocontainment of genetically modified LBPs is a critical aspect of designing them. A wide range of methods such as nutritional auxotrophy, transcriptional regulation pathways, kill switches have been reliably used for this purpose. While stable gut colonization can be beneficial in certain instances, obtaining a therapeutic effect from an engineered LBP is not intrinsically reliant on colonization. Some LBPs examined in clinical trials have been intentionally designed not to colonize the gut to improve their biocontainment.

An efficient delivery of LBPs remains a challenge due to physiological adversities. However, innovative strategies that use pharmaceutical formulations, genetic engineering techniques, and synergistic combination approaches are paving the way for improving delivery mechanisms. This will enhance therapeutic outcomes by increasing the survival rates following oral administration, extending residence time, accelerating colonization speed, and specifying colonization location. Understanding and implementing these strategies will significantly contribute to the advancement of this emerging field.

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Reference

1. Heavey, M. K., et al. Discovery and delivery strategies for engineered live biotherapeutic products. Trends in Biotechnology. 2021, 40(3), 354-369.

For Research Use Only. Not intended for use in food manufacturing or medical procedures (diagnostics or therapeutics). Do Not Use in Humans.