The Use of Amino Acid Linkers in the Conjugation of Paclitaxel with Hyaluronic Acid as Drug Delivery System: Synthesis, Self-Assembled Property, Drug Release, and In Vitro Efficiency

Abstract

Prodrugs synthesized as HA-amino acid-paclitaxel conjugates exhibited enhanced cytotoxicity in breast cancer cell lines and hence may have potential application as tumor-specific nanoparticulate therapeutic agents.

Paclitaxel-loaded hyaluronan solid nanoemulsions for enhanced treatment efficacy in ovarian cancer

“…Within 7 days of injection, a tumor could be observed in the left or right flank of the mouse. When the tumor grew to a size of approximately 100 mm 3 or more, the nude mice were divided into six groups (G1-G6, n=7 per group) of similar average tumor size. The groups were treated as follows: Group 1 (G1) physiological saline (control) group, Group 2 (G2) Taxol group (positive control, 20 mg/kg), Group 3 (G3) PTX-SN group (20 mg/kg), Group 4 (G4) PTX-HSN group (20 mg/kg), Group 5 (G5) PTX-SN group (50 mg/kg), and Group 6 (G6) PTX-HSN group (50 mg/kg).…”

“…Its mechanism of action involves interference in the normal breakdown of microtubules during cell division, thereby inducing apoptosis 1 and mitotic arrest, as well as affecting fundamental cellular functions including cell motility, cell transport, and mitosis. 2,3 PTX is a commonly used anticancer drug that possesses pharmacological activity when applied as a single therapeutic agent and is extensively used to treat ovarian, pancreatic, breast, non-small-cell lung, and other cancers. 4 However, due to its hydrophobicity, PTX has poor water solubility (1 µg/mL), which limits its clinical application.…”

“…Subsequently, 1 mL of each of the reconstituted PTX-SNs and PTX-HSNs (3 mg/mL) was added to the dialysis tubing attached to a support, and the release of PTX was determined according to Apparatus 2 of the Unites States Pharmacopeia (USP) dissolution method (paddle method). The release test was performed with 900 mL of the release medium at 100 rpm and 37°C; 1 mL of the released sample was collected at each time point (1,3,6,12,24,36,48,72,96,120, and 144 h). The content of PTX in each sample was measured using the HPLC method described.…”

Hyaluronic Acid Bioconjugates for the Delivery of Bioactive Molecules

“…HA-paclitaxel conjugates: (a) A hemisuccinate NHS activated ester of paclitaxel was linked to an HA-ADH derivative [29]; (b) A hemisuccinate NHS activated ester of paclitaxel was linked to an HA-EDA derivative [36]; (c) A 2′-paclitaxel-4-bromobutyrate was conjugate to HA [37]; (d) An amino acid-paclitaxel derivative was linked to HA activated by carbodiimide [44]; and (e) Paclitaxel was directly conjugated to carboxylic groups of HA by means of dicyclohexylcarbodiimide (DCC)/dimethylaminopyridine (DMAP), leading to polymeric micelles [45]. Xin, Wang and Xiang described the conjugation of paclitaxel onto HA using amino acid linkers ( Figure 3d) [44]. Firstly, the carboxylic group of the chosen amino acid was linked to the hydroxyl group of paclitaxel, and then, the amino group of the amino acid-paclitaxel derivative was grafted and conjugated to the carboxylic group of HA via EDC and NHS activation in DMF.…”

Development of hyaluronic acid derivatives for applications in biomedical engineering

“…HA is widely used for active drug targeting to the tumour cells thanks to the expression of CD44 by the majority of solid tumours. For example, the chemotherapeutic agent Paclitaxel has been conjugated to the HA and afterwards released into the tumoral cells in multiple ways: via an ester linkage easily hydrolysed by enzymes present in the body [109]; via amino acid linkers using carbodiimide chemistry [110]; via esterification after modification of paclitaxel with 4-bromobutanoic acid [111]; encapsulation in nanoparticles afterwards covalently grafted to HA [112].…”