Tumor extracellular acidity activated “off–on” release of bortezomib from a biocompatible dendrimer

Abstract

A nanoparticle with a specific response to tumor extracellular acidity provides a new option in the design of tumor-targeted delivery systems. In this study, we report such a pH-responsive polymer which realizes an "off-on" release of bortezomib in tumor acidic microenvironments. A dendrimer surface is grafted with a neutral shell to reduce its cellular uptake, and its interior is functionalized with catechol moieties. An anticancer drug, bortezomib, is loaded within the dendrimer interior via a boronate-catechol interaction. The bortezomib-loaded dendrimer is non-toxic to a number of cells under physiological conditions, but kills most of the cells in slightly acidic microenvironments. In vivo studies further prove that the bortezomib-loaded dendrimer significantly inhibits tumor growth while causing minimal systemic toxicity to the animals. Since there are a number of potent anticancer drugs containing the boronate structure, the polymeric vector in this study provides a versatile scaffold to design pH-responsive drug carriers for chemotherapy.

Medical Applications Based on Supramolecular Self-Assembled Materials From Tannic Acid

“…Compared with PBA, boric acid polymers are more often used to construct reversible-covalent borate ester bonds. Bortezomib (BTZ) is an effective and specific proteasome inhibitor for cancer treatment (Wang et al, 2015 ). Su et al ( 2011 ) coupled BTZ with a polymer carrier containing catechol through a reversible dynamic covalent borate ester bond and then synthesized a new type of cell-targeted and pH-sensitive polymer carrier by modifying biotin-targeted ligands that are selectively ingested by cancer cells through the mechanism mediated by cell surface receptors, thus delivering the anticancer drug BTZ to cancer cells.…”

“…However, the activity of BTZ against solid tumors is lower; systemic use will lead to a higher risk of adverse reactions, and BTZ resistance has been observed. Wang et al ( 2015 ) reported a pH-responsive polymer based on a polyamide dendrimer, which is functionalized by the catechol group inside the dendrimer and achieves the “off-on” release of BTZ in the slightly acidic tumor microenvironment through catechol–borate dynamic covalent bonding interactions with BTZ, allowing the therapeutic effect of BTZ in cancer treatment to be maintained while reducing its adverse reactions. Recently, in view of the factors that limit the clinical application of BTZ, such as low water solubility, instability, a non-specific distribution, and poor permeability to tumors, Zhao et al ( 2019a ) designed a new strategy without any organic synthesis and modification.…”

Polymeric Nanoparticles and Their Novel Modifications for Targeted Delivery of Bortezomib

“…pH-sensitivity pH-responsive manner of polymeric nanoparticles and BTZ as novel strategy, can be considered to be a promising method for optimizing loading and control release of this drug. Boronic acid group in BTZ is mainly responsible for the reaction with other moieties such as hydroxyl 27 or carbonyl 29 interactions with BTZ is high at low pH, so they choose potassium phosphate buffer at pH 6.0 as an optimum medium for obtaining best loading efficiency by providing a balance between osmotic and ionic characteristics of chitosan. 7 Sensitivity to pH is also an important factor in BTZ release in tumor microenvironment with acidic pH.…”

Doxorubicin-loaded redox-responsive amphiphilic dendritic porphyrin conjugates for chemotherapy and photodynamic therapy

“…Thus, photosensitizers for PDT should be little or no harm under light-free conditions, such as pormer sodium (Photofrin), 16 Visudyne and Foscan, which have been approved by the U.S. Food and Drug Administration (FDA). 11,17 As one of the most promising nanocarriers, dendritic macromolecules have been employed for cancer therapy, including dendritic polyesters, [18][19][20] poly(propylene imine), 21,22 polyamidoamine (PAMAM), [23][24][25][26] triazine dendrimers, 27,28 peptide dendrimers, [29][30][31][32] and dendritic polyglycerols (dPGs), 33,34 which are a class of macromolecules with a highly branched three-dimensional architecture, multi-functionalities, and potential applications in biomedicine, especially for drug delivery. These dendrimers as drug carriers could allow for the delivery of a higher drug loading content (DLC) and drug loading efficiency (DLE) with reduced cytotoxic side effect.…”