Enema ion compositions for enhancing colorectal drug delivery.
Delivering drugs to the colorectum by enema has advantages for treating or preventing both local and systemic diseases. However, the properties of the enema itself are not typically exploited for improving drug delivery. Sodium ions are actively pumped out of the lumen of the colon, which is followed by osmotically-driven water absorption, so we hypothesized that this natural mechanism could be exploited to drive nanoparticles and drugs to the colorectal tissue surface. Here, we report that sodium-based, absorption-inducing (hypotonic) enemas rapidly transport hydrophilic drugs and non-mucoadhesive, mucus penetrating nanoparticles (MPP), deep into the colorectal folds to reach virtually the entire colorectal epithelial surface. In contrast, isotonic and secretion-inducing (hypertonic) vehicles led to non-uniform, poor surface coverage. Sodium-based enemas induced rapid fluid absorption even when moderately hyper-osmolal (~350 mOsm) compared to blood (~300 mOsm), which suggests that active sodium absorption plays a key role in osmosis-driven fluid uptake. We then used tenofovir, an antiretroviral drug in clinical trials for preventing HIV, to test the effects of enema composition on local and systemic drug delivery. We found that strongly hypotonic and hypertonic enemas caused rapid systemic drug uptake, whereas moderately hypotonic enemas with ion compositions similar to feces resulted in high local tissue levels with minimal systemic drug exposure. Similarly, moderately hypotonic enemas provided improved local drug retention in colorectal tissue, whereas hypertonic and isotonic enemas provided markedly reduced drug retention in colorectal tissue. Lastly, we found that moderately hypotonic enema formulations caused little to no detectable epithelial damage, while hypertonic solutions caused significant damage, including epithelial sloughing; the epithelial damage caused increased systemic drug absorption and penetration of MPP into colorectal tissue, a potential advantage in certain drug delivery applications. In summary, we illustrate that enema composition can be adjusted to maximize local versus systemic drug delivery, and that mildly hypotonic, sodium-based vehicles can provide uniform drug and MPP delivery in the colon that maximizes local drug concentrations.
Center for Nanomedicine, Johns Hopkins University School of Medicine, 400N. Broadway, Baltimore, MD 21231 USA; Department of Biomedical Engineering, Johns Hopkins University School of Medicine, 720 Rutland Avenue, Baltimore, MD 21205 USA.
Katharina
K
Maisel
Center for Nanomedicine, Johns Hopkins University School of Medicine, 400N. Broadway, Baltimore, MD 21231 USA; Department of Chemical and Biomolecular Engineering, Johns Hopkins University, 3400 N. Charles Street, Baltimore, MD 21218 USA.
Sumon
S
Chattopadhyay
Department of Biophysics, Johns Hopkins University, 3400 N. Charles Street, Baltimore, MD 21218 USA; ReProtect, Inc, 703 Stags Head Road, Baltimore, MD 21286 USA.
Thomas
T
Moench
Department of Clinical Pharmacology, Johns Hopkins University School of Medicine, 600 N. Wolfe Street, Baltimore, MD 21287, USA.
Craig
C
Hendrix
Center for Nanomedicine, Johns Hopkins University School of Medicine, 400N. Broadway, Baltimore, MD 21231 USA; Department of Biophysics, Johns Hopkins University, 3400 N. Charles Street, Baltimore, MD 21218 USA.
Richard
R
Cone
Center for Nanomedicine, Johns Hopkins University School of Medicine, 400N. Broadway, Baltimore, MD 21231 USA; Department of Chemical and Biomolecular Engineering, Johns Hopkins University, 3400 N. Charles Street, Baltimore, MD 21218 USA; Department of Ophthalmology, The Wilmer Eye Institute, Johns Hopkins University School of Medicine, 400 N. Broadway, Baltimore, MD 21231, USA; Center for Cancer Nanotechnology Excellence, the Institute for NanoBioTechnology, Johns Hopkins University, 3400 N Charles Street, Baltimore, MD 21218, USA. Electronic address: lensign@jhmi.edu.
Laura M
LM
Ensign
Center for Nanomedicine, Johns Hopkins University School of Medicine, 400N. Broadway, Baltimore, MD 21231 USA; Department of Biomedical Engineering, Johns Hopkins University School of Medicine, 720 Rutland Avenue, Baltimore, MD 21205 USA; Department of Chemical and Biomolecular Engineering, Johns Hopkins University, 3400 N. Charles Street, Baltimore, MD 21218 USA; Department of Ophthalmology, The Wilmer Eye Institute, Johns Hopkins University School of Medicine, 400 N. Broadway, Baltimore, MD 21231, USA; Center for Cancer Nanotechnology Excellence, the Institute for NanoBioTechnology, Johns Hopkins University, 3400 N Charles Street, Baltimore, MD 21218, USA; Departments of Neurosurgery, Oncology, and Pharmacology & Molecular Sciences, Johns Hopkins University School of Medicine, 600 N. Wolfe Street, Baltimore, MD 21287, USA. Electronic address: hanes@jhmi.edu.
Justin
J
Hanes
D000285:Administration, Rectal; D000818:Animals; D044966:Anti-Retroviral Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D003106:Colon / Q000378:metabolism; D016503:Drug Delivery Systems; D004733:Enema; D005260:Female; D007038:Hypotonic Solutions; D051379:Mice; D009093:Mucus / Q000378:metabolism; D053758:Nanoparticles / Q000737:chemistry; D009994:Osmolar Concentration; D011092:Polyethylene Glycols / Q000737:chemistry; D011137:Polystyrenes / Q000737:chemistry; D011188:Potassium / Q000008:administration & dosage / Q000737:chemistry; D012964:Sodium / Q000008:administration & dosage / Q000737:chemistry; D000068698:Tenofovir / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics
D044966:Anti-Retroviral Agents; D007038:Hypotonic Solutions; D011137:Polystyrenes; D011092:Polyethylene Glycols; D000068698:Tenofovir; D012964:Sodium; D011188:Potassium
Colon; Gastrointestinal tract; Microbicide; Pre-exposure prophylaxis