Novel Pullulan Bioconjugate for Selective Breast Cancer Bone Metastases Treatment

Abstract

A novel polysaccharide bioconjugate was designed to selectively target breast cancer bone metastases using a bisphosphonate moiety (alendronate, ALN). Paclitaxel (PTX) was first covalently conjugated to pullulan (Pull) through a Cathepsin K-sensitive tetrapeptide spacer followed by a self-immolative aminobenzyl alcohol spacer to obtain Pull-(GGPNle-φ-PTX). ALN was then conjugated to the polymeric backbone of Pull-(GGPNle-φ-PTX) via a PEG spacer. The final bioconjugate Pull-(GGPNle-φ-PTX)-(PEG-ALN) was found to assemble into colloidal spherical structures, which were physically and chemically stable under physiological conditions. In vitro studies showed that Pull-(GGPNle-φ-PTX)-(PEG-ALN) had strong affinity for hydroxyapatite, which simulates the bone tissue. Paclitaxel was rapidly released from the bioconjugate by Cathepsin K cleavage under pathological conditions. All studies performed using human MDA-MB-231-BM (bone metastases-originated clone), murine 4T1 breast cancer cells, murine K7M2, and human SAOS-2 osteosarcoma cells showed that the bioconjugate exerted an enhanced antiproliferative activity compared to the conjugate without the ALN. Furthermore, the nanoconjugate inhibited the migration of cancer cells and further displayed potent anti-angiogenic activity. In conclusion, the results showed that this conjugate has an excellent potential for selective treatment of bone neoplasms such as breast cancer bone metastases and osteosarcoma.

Synthetic Procedures Leading towards Aminobisphosphonates

“…This should ensure release of paclitaxel in bones. Then, bisphosphonate was covalently conjugated to the sugar chain via a polyethyleneglycol chain, using a technique similar to that described above (identical to those shown in Scheme 34) [155]. This system exhibited strong antiproliferative action against several cancer cell lines.…”

Galactosylated pullulan–curcumin conjugate micelles for site specific anticancer activity to hepatocarcinoma cells

“…It is formed from -1,4 linked glucose units that are included in a -1,6 linked maltotriose unit. Self assembled nanoparticles from pullulan were prepared by hydrophobic modification with cholesterol [14], diethylaminoethyl [15], maleic [16] and acetate [17] groups and these nanoparticles were used for application in gene delivery, drug delivery etc [17][18][19][20][21].…”

“…Compared to the non-targeted counterparts, polymer drug conjugates with targeting ligands show enhanced toxicity to the targeted site while being less toxic to other cells [21][22][23]. Though pullulan has been used for preparing different drug conjugates, suitability of this highly water soluble polysaccharide for conjugation to curcumin is not yet attempted.…”

Design, Synthesis, and Photophysical Properties of Pyrroloquinoline‐Based Compounds Showing Strong Blue Fluorescence as Potential Dyes for Biomedical Applications

“…Pullulan is a biocompatible polysaccharide that has been widely investigated to produce innovative colloidal systems for the delivery of both small drugs and biological molecules. Pullulan‐based drug delivery systems include macromolecular bioconjugates, nanoparticles, nanovesicles, and supramolecular assemblies . Pullulan is a suitable scaffold for chemical conjugation because it can be easily activated to covalently attach molecules, including labeling agents along the backbone.…”

“…Pullulan-basedd rug delivery systems include macromolecular bioconjugates, nanoparticles, nanovesicles, and supramolecular assemblies. [10,12] Pullulan is as uitable scaffold for chemical conjugation because it can be easily activated to covalently attach molecules, including labeling agents along the backbone. Therefore, pullulan was considered asuitable model colloid for labeling and biological studies.…”