Hyaluronic Acid Molecular Weight Determines Lung Clearance and Biodistribution after Instillation

Abstract

Hyaluronic acid (HA) has emerged as a versatile polymer for drug delivery. Multiple commercial products utilize HA, it can be obtained in a variety of molecular weights, and it offers chemical handles for cross-linkers, drugs, or imaging agents. Previous studies have investigated multiple administration routes, but the absorption, biodistribution, and pharmacokinetics of HA after delivery to the lung is relatively unknown. Here, pharmacokinetic parameters were investigated by delivering different molecular weights of HA (between 7 and 741 kDa) to the lungs of mice. HA was labeled with either a near-infrared dye or with iodine-125 conjugated to HA using a tyrosine linker. In initial studies, dye-labeled HA was instilled into the lungs and fluorescent images of organs were collected at 1, 8, and 24 h post administration. Data suggested longer lung persistence of higher molecular weight HA, but signal diminished for all molecular weights at 8 h. To better quantitate pharmacokinetic parameters, different molecular weights of iodine-125 labeled HA were instilled and organ radioactivity was determined after 1, 2, 4, 6, and 8 h. The data showed that, after instillation, the lungs contained the highest levels of HA, as expected, followed by the gastrointestinal tract. Smaller molecular weights of HA showed more rapid systemic distribution, while 67 and 215 kDa HA showed longer persistence in the lungs. Lung exposure appeared to be optimum in this size range due to the rapid absorption of <67 kDa HA and the poor lung penetration and mucociliary clearance of viscous solutions of HA > 215 kDa. The versatility of HA molecular weight and conjugation chemistries may, therefore, provide new opportunities to extend pulmonary drug exposure and potentially facilitate access to lymph nodes draining the pulmonary bed.

Colorectal cancer‐associated ~ 6 kDa hyaluronan serves as a novel biomarker for cancer progression and metastasis

“…Evidence has proven that HA fragments abnormally accumulate in cancer tissues and can be secreted into blood circulation [22]. Indeed, according to previous reports from us and others, LMW-HA has been found in the sera of patients with renal and breast cancer and has shown promise in predicting cancer progression [23,24].…”

Polymer-drug conjugates as inhalable drug delivery systems: A review

“…5[I].) [93]. In comparison, a very high molecular weight HA construct (741 kDa) was rapidly cleared from the lungs via mucociliary clearance ( Fig.…”

“…[II] Time course of lung clearance of IR-labelled HA after pulmonary administration. Each point is the average of at least three animals (Reproduced with permission from reference [93]). …”

“…Recent evidence showed that pulmonary delivery of HA-conjugated anticancer drugs also provides control over lymphatic cancer metastases [93,98,100]. Nanoparticles prepared using HA with a molecular weight of approx.…”

“…Nanoparticles prepared using HA with a molecular weight of approx. 75 kDa and a particle size below 50 nm may access the lymphatic system [93]. High molecular weight HA also breaks into small molecular weight components by hyaluronidases that can also facilitate the entry of HAconjugated drugs into the lymphatic circulation [101].…”