Abstract
BackgroundIt is extremely difficult to develop targeted treatments for triple-negative breast (TNB) cancer, because these cells do not express any of the key biomarkers usually exploited for this goal.ResultsIn this work, we develop a solution in the form of a cascade responsive nanoplatform based on thermo-sensitive poly(N-vinylcaprolactam) (PNVCL)-chitosan (CS) nanoparticles (NPs). These are further modified with the cell penetrating peptide (CPP) and loaded with the chemotherapeutic drug doxorubicin (DOX). The base copolymer was optimized to undergo a phase change at the elevated temperatures of the tumor microenvironment. The acid-responsive properties of CS provide a second trigger for drug release, and the inclusion of CPP should ensure the formulations accumulate in cancerous tissue. The resultant CPP-CS-co-PNVCL NPs could self-assemble in aqueous media into spherical NPs of size < 200 nm and with low polydispersity. They are able to accommodate a high DOX loading (14.8% w/w). The NPs are found to be selectively taken up by cancerous cells both in vitro and in vivo, and result in less off-target cytotoxicity than treatment with DOX alone. In vivo experiments employing a TNB xenograft mouse model demonstrated a significant reduction in tumor volume and prolonging of life span, with no obvious systemic toxicity.ConclusionsThe system developed in this work has the potential to provide new therapies for hard-to-treat cancers.
Highlights
It is extremely difficult to develop targeted treatments for triple-negative breast (TNB) cancer, because these cells do not express any of the key biomarkers usually exploited for this goal
Phase transition behavior of cell penetrating peptide (CPP)‐CS‐co‐PNVCL copolymers Since the phase transition temperature is a key parameter for targeted delivery to the tumor, the lower critical solution temperature (LCST) of the CPPCS-co-PNVCL materials in aqueous solution was first investigated
CPP-CS-co-PNVCL1 was transparent at the physiological temperature (37 °C) but became turbid once the temperature was raised to 40 °C
Summary
It is extremely difficult to develop targeted treatments for triple-negative breast (TNB) cancer, because these cells do not express any of the key biomarkers usually exploited for this goal. Triple-negative breast (TNB) cancer, which is defined by a lack of expression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal To address these issues, nanoscale drug delivery systems (DDSs) have been widely explored for chemotherapy. Polymer nanoassemblies based on amphiphilic block copolymers which can self-assemble into “core–shell” structures in aqueous solution permit a hydrophobic drug cargo to be loaded into the core of the system, and thereby can enhance its water solubility [13, 14] This is a major benefit given that many of the most potent chemotherapeutic active ingredients are poorly water soluble: their hydrophobicity is a major obstacle in ensuring they can circulate in the blood, for instance in the case of doxorubicin (DOX), an anthracycline anticancer drug approved by the Food and Drug Administration (FDA) which has extremely low water solubility [15, 16]
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