A hyaluronic acid–pentamidine bioconjugate as a macrophage mediated drug targeting delivery system for the treatment of leishmaniasis

Abstract

Leishmaniasis is still a serious public health problem worldwide, especially in tropical areas where this infectious disease is endemic. The most severe form of the disease (i.e. visceral) can claim victims if left untreated and the few accessible drugs have several drawbacks including major side effects and parenteral administration. In this context, the investigation of new delivery modalities which might reduce the toxicity and increase the bioavailability of the drugs currently on the market represents a valid strategy to counter these problems. Herein we present the development of a macrophage mediated drug targeting delivery system by conjugating the anti-leishmanial drug pentamidine (Pent) with the biocompatible polymer hyaluronic acid (HA), the latter employed at the same time as a delivery platform and targeting scaffold. Biological assays against Leishmania major amastigote-infected macrophages and primary bone marrow derived macrophages (BMDM) confirmed the validity of our strategy as the resulting bioconjugate HA-Pent increased both the potency and the selectivity index of the drug.

“Click” on PLGA‐PEG and hyaluronic acid: Gaining access to anti‐leishmanial pentamidine bioconjugates

“…The PP‐Pent average molecular masses lowering, respect to starting PLGA, is probably due to the protract trans‐esterification processes occurring during PP synthesis. The average Mw of HA and its derivatives were determined by means of SEC‐MALS technique . The analysis of HA after ion exchange resin treatment showed a molar mass distribution with an average molecular weight of about 55.0 kDa and a poly‐dispersity index of 1.35.…”

“…The average Mw of HA and its derivatives were determined by means of SEC-MALS technique. 16 The analysis of HA after ion exchange resin treatment showed a molar mass distribution with an average molecular weight of about 55.0 kDa and a poly-dispersity index of 1.35. Conversely, for HA-Pent a decreased elution volume was detected, indicating an increase of the molecular mass (Mw 5 290 kDa, Mn 5 140 kDa), due to the cross-linking click reactions between HA-Alk and Pent-N 3 .…”

“…1 Preparation of Pent free base Pent free base was obtained from Pent isethionate. 16 Pent isethionate (5 g, 8.43 mmol) was dissolved in 100 mL of distilled water under vigorous stirring. Sodium hydroxide was gradually added until the pH of the solution was adjusted to 11.…”

Hyaluronan-binding peptide for targeting peritoneal carcinomatosis

“…HA is recruited to macrophages and internalized through receptors such as CD44 23 and HA receptors for endocytosis (HARE/Stab2). 24 …”

Ensemble‐based ADME–Tox profiling and virtual screening for the discovery of new inhibitors of the Leishmania mexicana cysteine protease CPB2.8ΔCTE

“…If the Sb-based drugs turn out to be ineffective, pentamidine, amphotericin, paromomycin, and miltefosine are recommended as second-line drugs of choice, but unfortunately, they are also toxic and require long-term treatments. [2][3][4] Although leishmaniasis presents high rates of morbidity and mortality only in endemic areas of tropics and subtropics, it is considered a global health concern due to the fact that several risk factors contribute to the spread and proliferation of the causative Leishmania species and its vector (i.e., phlebotomine sandfly). [5] In view of that, and in the absence of an effective vaccine, there is a continuous interest in the identification of new drug targets and the development of new drug candidates for the treatment of this disease.…”