Crosslinked casein micelles bound paclitaxel as enzyme activated intracellular drug delivery systems for cancer therapy

[Display omitted] •Cross-linked casein micelles (CCM) were prepared using casein self-assembly properties.•The CCM were degraded immediately after exposition to proteases.•The CCM were able to load paclitaxel (PTX) in their structure.•In vitro studies in models cells showed that CCM@PTX improve the toxicity of PTX.•CCM@PTX have potential for parenteral administration to treat cancers with proteases overexpression. Nanomedicine for cancer therapy is a successful tool to diminish the side effect of chemotherapeutics such as paclitaxel (PTX). In this regard, Abraxane®, a human serum albumin (HSA)-based nanomedicine system has shown lesser side effects than Taxol®. However, the large-scale production of HSA protein is limited and expensive, which is traduced in a high cost of the treatments in clinical applications. Thus, the use of easily-available alternative nanocarriers could increment the accessibility of patients to nanomedicine for cancer treatments. Casein is a low-cost protein able to self-assemble into micelles which could efficiently encapsulate PTX into their structure. In this work, the synthesis of chemically crosslinked casein micelles (CCM), used to prepare PTX-based nanoformulations, is presented. CCM@PTX nanoformulations showed promising results in vitro to be applied as nanomedicine for cancer therapy. Thus, the obtained nanoformulations are great candidates to be parenterally administered, accumulate in tumor by passive targeting without leakage of PTX in plasma, and release the drug within the tumor microenvironment, in response to overexpressed proteases such as trypsin.