The short half-life in the GI tract necessitates an excess of drugs causing side effects of oral formulations. Here, we report the development and deployment of Bacterioboat, which consists of surface-encapsulated mesoporous nanoparticles on metabolically active Lactobacillus reuteri as a drug carrier suitable for oral administration. Bacterioboat showed up to 16% drug loading of its dry weight, intestinal anchorage around alveoli regions, sustained release, and stability in physiological conditions up to 24 hours. In vivo studies showed that oral delivery of 5-fluorouracil leads to increased potency, resulting in improved shrinkage of solid tumors, enhanced life expectancy, and reduced side effects. This novel design and development make this system ideal for orally administrable drugs with low solubility or permeability or both and even making them effective at a lower dose.

The oral route is the most convenient route of drug administration and almost 80 % of the drugs are administered through this route. Despite many advantages like self-administrable, convenient, economic, pain-free, non-invasive, etc, the oral route is a major challenge for drugs which has low permeability through the GI tract leading to absorption of only 3-10% of the administered dose and reduced bioavailability. Therefore, due to limited half-life (~30 mins) in the stomach and small intestine, to achieve effective response excess of drugs need to be administrated through an oral route which causes many side effects including irritable bowel syndrome, hemorrhoids, gastrointestinal ulcers, and cancer, Cohn's disease, ulcerative colitis, etc. Besides mixing of the un-metabolized drug to the environment like soil and drinking water causes bio-magnifications and infer the development of antibiotic resistance in microorganisms. Therefore, an increase of half-life in the GI tract would be a great solution to solve this problem. Here in this work, we show the use of surface encapsulated mesoporous (2-3 nm) carbohydrate nanoparticles of (15-25 nm in size) on metabolically active Lactobacillus reuteri, a GRAS bacterium, as a drug carrier vehicle suitable for oral administration. We have further demonstrated the use of bacteria mediated drug delivery system for enhancing the potency of 5-fluorouracil against Sarcoma-180 cancer. The bacterial surface encapsulated nanoparticles particles showed 12-15% drug loading capacity of its dry weight. The particles also showed excellent stability up to 48 h in simulated gastric and intestinal fluid. Further, the particles showed sustained release of the drug for up to 16 h, where after an initial blast (release up to 30 %) between 30 min-1 h a steady release of drug was obtained for up to 6.5 to 7 h, where 95% of the drug got released within that window. The pre-clinical study showed anchorage of drug-loaded surface encapsulated microbes to the mice intestinal alveolar regions after feeding through the oral route. Further, a study using murine Sarcoma-180 tumor model showed enhancement of life span and enhanced shrinkage of the Sarcoma-180 solid tumor volume (up to -95%) at optimal dose 50 mg/Kg dose, in comparison with control only ~75% throughout 10 days' treatment. Up to 75 % reduction of tumor volume was also observed in suboptimal dose (25 mg/kg) using the microbial vehicle. Reduction of hepatic and nephrotic toxicity was also evident from the blood parameters analysis and histological analysis was also prominent using this delivery tool. This novel design and development make this system ideal for use in orally administrable drug shaving low solubility or permeability or both. Citation Format: Parmandeep Kaur, Diptiman Choudhury. Gut microflora mediated novel oral drug delivery system [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 310.

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