Intracellular and extracellular enzymatic responsive micelle for intelligent therapy of cancer

Abstract

Yi Liu 2 ( ), and Jie Pan 1 ( ) Recently, the incidence of cancer keeps increasing, seriously endangers human health, and has evolved into the main culprit of human death. Conventional chemotherapeutic drugs, such as paclitaxel and doxorubicin (DOX), have some disadvantages, including low therapeutic effect, poor water solubility, high toxic side effects, short blood circulation time in the body, and so on. To improve the anti-tumor effect of the drug in vivo and reduce its side effects on the body, researchers have designed and developed a variety of responsive nanocarriers. In this work, we synthesized D-α-tocopherol polyethylene glycol 3350 succinate (TPGS 3350 )-Gly-Pro-Leu-Gly-Val-Arg (GPLGVR)-DOX (TPD) prodrugs in response to extracellular enzymes of matrix metalloproteinase (MMP-9) in the tumor microenvironment and FA-Asp-Glu-Val-Asp (DEVD)-DOX (FPD) prodrugs responsive to intracellular enzymes of caspase-3. Then, intracellular and extracellular enzyme-responsive TPD&FPD micelles with DOX (TPD&FPD&D) were successfully prepared through dialysis method. The outer layer of TPGS 3350 can prolong the blood circulation time of micelles in vivo, followed by accumulation of micelles at tumor tissue through enhanced permeability and retention (EPR) effect. The peptide of GPLGVR can be cleaved by MMP-9 enzymes to remove the outer layer of TPGS 3350 , exposing the targeting molecule of folate, and then the micelles are engulfed by tumor cells through folate receptor-mediated endocytosis. After entering the tumor cells, the free DOX loaded in the micelles is released, which induces tumor cell apoptosis to activate caspase-3 in the cells, cutting the peptide DEVD to accelerate the intracellular release of the DOX, which further enhances cytotoxicity to improve antitumor effect.

Shoot the Arrow at the Target: Innovative Stimulus-Responsive Smart Nanocarriers for Cancer Therapy

“…This investigation demonstrated it's desirable to utilize enzyme-sensitive peptide nanostructures in practical targeted drug delivery, which had significant prospects in biomedical cancer therapy. In addition, Wan et al constructed dual enzyme-responsive micelles for the first time by physically loading enzyme-responsive substances into the micelles via π-π stacking, and obtained DOX micelles consisting of intra-and extracellular enzyme-responsive TPD&FPD&D micelles by dialysis preparation [59]. Two of the enzyme-responsive substances were D-α-tocopherol polyethylene glycol 3350 succinate (TPGS3350)-Gly-Pro-Leu-Gly-Val-Arg (GPLGVR)-DOX (TPD) precursors specifically responding to the overexpression of MMP-9 in the TME, and FA-Asp-Glu-Val-Asp (DEVD)-DOX (FPD) precursors responding to the caspase-3, respectively (Figure 4B).…”

Phototriggered Cytotoxicity of Ferrocene-Based Micelles – A Nonconventional Approach to Phototherapy

“…In the biomedical field, activatable micelles are highly sought after for the greater control they offer over the release of the embarked payload. The activation process can be triggered by specific endogenous stimuli such as pH, reactive oxygen species (ROS), or enzymes . Although internal stimuli are currently being investigated for local drug delivery applied to cancer treatment, they rely on the tumor microenvironment, which is variable from patient to patient, but also from tumor type to tumor type and even within the tumor itself. , Therefore, nanoparticles that are not activated by fluctuating internal triggers but rather by controllable external ones should perform more reliably in different tumor contexts.…”

Visualization and Quantification of Drug Release by GSH-Responsive Multimodal Integrated Micelles

“…To ensure controlled drug release, stimulus-responsive polymeric micelle drug delivery systems have been investigated. These systems offer enhanced stability in normal tissues and rapid drug release in tumor microenvironments. − Polymeric prodrug micelles containing chemotherapeutic drugs linked with cleavable chemical bonds prevent drug leakage during circulation and respond to stimuli at the tumor site, triggering drug release. − Notably, GSH is crucial in maintaining intracellular redox balance and is associated with various diseases. − Hence, selective detection and quantification of GSH hold valuable information for disease prognosis . Several GSH-responsive drug release systems have been rationally designed for cancer treatment due to the significant difference between intracellular and extracellular GSH concentrations, and tumor cells contain a higher concentration of GSH, which is 4–7 times that of normal cells …”