Tumor‐activated prodrug (TAP)‐conjugated nanoparticles with cleavable domains for safe doxorubicin delivery

Abstract

A major issue in chemotherapy is the lack of specificity of many antitumor drugs, which cause severe side effects and an impaired therapeutic response. Here we report on the design and characterization of model tumor activated prodrug-conjugated polystyrene (PS) nanoparticles (TAP-NPs) for the release of doxorubicin (Dox) triggered by matrix metalloprotease-2 (MMP2) enzyme, which is overexpressed in the extracellular matrix of tumors. In particular, TAP-NPs were produced by attaching Dox to poly(ethylene glycol) (PEG) through two MMP2-cleavable enzymes. The resulting adduct was then tethered to PS NPs. Results showed that Dox release was actually triggered by MMP2 cleavage and was dependent on enzyme concentration, with a plateau around 20 nM. Furthermore, significant cell cytotoxicity was observed towards three cell lines only in the presence of MMP2, but not in cells without enzyme pre-treatment, even after NP internalization by cells. These findings indicate the potential of TAP-NPs as suitable nanocarriers for an on demand, tumor--specific delivery of antitumor drugs after the response to an endogenous stimulus. Further advancements will focus on the translation of this production technology to biodegradable systems for the safe transport of cytotoxic drug to tumor tissues.

DePEGylation strategies to increase cancer nanomedicine efficacy

“…Liposomes [139][140][141][142][143][144][145] Quantum dots (QDs) [157] Polymersomes [158] Magnetic nanoparticles [159] Micelles [146][147][148][149][150][151][152][153][154][155][156] [ 160,161] External Light Liposomes [163] MSN [164] Micelles [168] [ 63,[165][166][167]169]…”

Experimental Studies and Modeling of the Degradation Process of Poly(Lactic-co-Glycolic Acid) Microspheres for Sustained Protein Release

“…Nevertheless, to the best of ourknowledge, none of the models recently appeared in literature proposed to simulate the advancement of MS degradation front withthe measurements of the radius of the degraded spheres, as in the present study. In this work, model equations have been defined based on the autocatalytic mechanism of PLGA degradation kinetics, which has been described by a Michaelis and Menten reaction, following a previous publication [39]. The model takes into account the reaction between soluble acids and the polymer to define the rate of generation of soluble oligomers and monomers.…”

Polymeric Nanocarriers: A Transformation in Doxorubicin Therapies

“…Drug release from drug delivery system within a two-step mechanism: drug delivery system is cleaved by enzyme (A), and further cleagaved to release free drug (B). particles (TAP-NPs), containing PLGSYL and GPLGIAGQN peptides, demonstrated substantial cytotoxicity toward HT1080, HDF, and HUVEC cells in a time-dependent manner [107]. More prominent effects were observed for HT1080 cells than for healthy and primary cells, and stronger inhibition was reported for TAP-NPs functionalized by GPLGIAGQN than by PLGSYL.…”