Acid-labile poly(ethylene glycol) shell of hydrazone-containing biodegradable polymeric micelles facilitating anticancer drug delivery

Abstract

Biodegradable pH-sensitive amphiphilic block polymer (mPEG-Hyde-PLGA) was synthesized via ring-opening polymerization, initiated from a hydrazone-containing macro-initiator. In this way, a pH-sensitive hydrazone bond was inserted into the backbone of block copolymer, linking hydrophilic poly(ethylene glycol) segment and hydrophobic poly(lactic-co-glycolic acid) segment. The copolymer self-assembled to form stable micelles with mean diameters below 100 nm and served as a drug delivery system for doxorubicin, with drug loading content of 5.3%. pH sensitivity of the hydrazone-containing micelles was investigated by changes in diameter and size distribution observed by dynamic light scattering measurements when the micelles were encountered to acidic medium. Small pieces and larger aggregates were found by transmission electron microscopy resulting from the disassociation of the micelles in acidic conditions. It was also noted that doxorubicin release from the pH-sensitive micelles is significantly faster at pH 4.0 and pH 5.0 compared to pH 7.4, while almost no difference was detected in the case of pH non-sensitive micelles. MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assays on HepG-2 and MCF-7 cells revealed that doxorubicin-loaded pH-sensitive micelles had higher antitumor activity than pH-insensitive ones. This pH-sensitive drug delivery system based on hydrazonecontaining block copolymer has been proved as a promising drug formulation for cancer therapy.

Acidic pH-Triggered Release of Doxorubicin from Ligand-Decorated Polymeric Micelles Potentiates Efficacy against Cancer Cells

“…We developed a FA-decorated and doxorubicin-conjugated polymeric micelle which exhibits enhanced nuclear delivery of doxorubicin (to its site of action) in FR-overexpressed cancer cells. Here, the doxorubicin is covalently bound with the hydrophobic part of the amphiphilic polymeric backbone via a hydrazone bond, which is particularly important to offer the chemical stability of the drug, protecting it from degradation and premature release, which extends the drug’s half-life, maintains its potency, and finally ensures its efficacy during the therapy process. – Moreover, FA binds to FRs overexpressed on the cancer cells, leading to enhanced polymeric micelle internalization. ,, The entire chemical approach contributes to the generation of small DDS (30–40 nm diameter), which is the key to fostering their interaction with the target cells by facilitating the process of receptor–ligand interactions and bindings. After the endocytosis process, once the micelle is inside the endolysosomal compartment, it encounters an acidic pH.…”

pH-Sensitive Biomaterials for Drug Delivery

“…Hydrazone is formed by condensation of aldehydes, ketones, or hydrazine. Similar to imine bonds, the hydrazone bonds are also a class of covalent bonds which are acidic responsive [43][44][45][46][47]. As hydrazone bonds are easily hydrolytic under acidic conditions, they have been widely utilized in the construction of acidic sensitive carriers for responsive formulations [48,49].…”

A New Class of Tunable Acid-Sensitive Linkers for Native Drug Release Based on the Trityl Protecting Group

“…Acid-sensitive API carrier systems containing hydrazone, − acetal, , orthoester, , or imine − moieties have been developed and investigated. These molecular moieties are not easily chemically modified, which limits the possibilities to adjust and tailor the release kinetics of APIs.…”