Hyaluronic Acid-Tacrolimus Bioconjugate: Synthesis, Characterization, and Pharmacokinetic Investigation of an Acid-Responsive Macromolecular Prodrug

Abstract

Polymer-drug conjugates have been the cornerstone of several drug delivery systems owing to their numerous benefits such as improved drug solubilization, controlled release, increased efficacy, and improved pharmacokinetics. Herein, an acid-responsive macromolecular prodrug was synthesized by conjugation of Tacrolimus (TAC; FK506) with chemically modified hyaluronic acid (HA), and its physicochemical and pharmacokinetic properties were studied in detail. The prepared conjugate (HA-ADH-TAC) showed 1% drug loading, sustained drug release, and significantly enhanced solubility for the investigated drug. Additionally, cellular uptake study indicated augmented uptake of this conjugate, and hemolysis assay showed biocompatibility of the developed prodrug. Further, the pharmacokinetic behavior of the conjugate was investigated, and it was observed that pharmacokinetic parameters with the conjugate were improved. The results indicate that the developed HA-tacrolimus conjugate has the edge over the plain drug in terms of improved physicochemical properties and favorable pharmacokinetic response.

Synergistic combination of PMBA and 5-fluorouracil (5-FU) in targeting mutant KRAS in 2D and 3D colorectal cancer cells

“…Quantitation of PMBA was carried out by J o u r n a l P r e -p r o o f 7 using LC-MS/MS (Make:Shimadzu; Model:8030). Plasma concentrations of PMBA at respective time points were obtained and calculation was done for various pharmacokinetic parameters by non-compartmental analysis using PK solution software (Summit Research Services, Colorado, USA) (Dheer et al, 2019).…”

Fungal Keratitis Treatment Using Drug-Loaded Hyaluronic Acid Microgels

“…17,18 Natural polymers based on hyaluronic acid (HA) and HA-derived micro/nanogels gained special attention for these active agent transport applications because of the remarkable intrinsic characteristics of HA. 19 Thus, HA is biocompatible, biodegradable, and nontoxic and has smart biodistribution and natural targeting ability, e.g., for CD44 receptors; 20 modifiable surface chemistry and morphology. 21,22 The chemical structure of HA, consisting of D-glucuronic acid and N-acetyl-D-glucosamine repeating disaccharide units, is suitable for conjugation reactions with various drug molecules through hydroxyl or carboxylic acid groups.…”

“…Because of the high drug-loading capacity and high cumulative release capability with tunable drug loading/delivery abilities, drug carrier materials based on cross-linked polymeric structures have recently attracted much interest in the last two decades. , Natural polymers based on hyaluronic acid (HA) and HA-derived micro/nanogels gained special attention for these active agent transport applications because of the remarkable intrinsic characteristics of HA . Thus, HA is biocompatible, biodegradable, and nontoxic and has smart biodistribution and natural targeting ability, e.g., for CD44 receptors; also, HA-derived micro/nanogels have modifiable surface chemistry and morphology. , The chemical structure of HA, consisting of d -glucuronic acid and N -acetyl- d -glucosamine repeating disaccharide units, is suitable for conjugation reactions with various drug molecules through hydroxyl or carboxylic acid groups .…”

2‐Isoxazolines: A Synthetic and Medicinal Overview

“…also reported the use of the isoxazoline moiety in water‐soluble PEG‐based polymers for drug delivery in cancer therapy [43] . Moreover, various drug delivery systems have been used by many research groups to explore the potential of these nitrogen‐containing heterocyclic systems in drug delivery [44–47] …”