Hyaluronic acid functional amphipathic and redox-responsive polymer particles for the co-delivery of doxorubicin and cyclopamine to eradicate breast cancer cells and cancer stem cells

Abstract

Cancer stem cells (CSCs) have the ability to transform into bulk cancer cells, to promote tumor growth and establish tumor metastasis. To effectively inhibit tumor growth and prevent metastasis, treatments with conventional chemotherapy drugs should be combined with CSC targeted drugs. In this study, we describe the synthesis and characterization of a new amphiphilic polymer, hyaluronic acid-cystamine-polylactic-co-glycolic acid (HA-SS-PLGA), composed of a hydrophobic PLGA head and a hydrophilic HA segment linked by a bioreducible disulfide bond. With a double emulsion method, a nano delivery system was constructed to deliver doxorubicin (DOX) and cyclopamine (CYC, a primary inhibitor of the hedgehog signaling pathway of CSCs) to both a CD44-overexpressing breast CSC subpopulation and bulk breast cancer cells and allow an on-demand release. The resulting drug-loaded NPs exhibited a redox-responsive drug release profile. Dual drug-loaded particles potently diminished the number and size of tumorspheres and HA showed a targeting effect towards breast CSCs. In vivo combination therapy further demonstrated a remarkable synergistic anti-tumor effect and prolonged survival compared to mono-therapy using the orthotopic mammary fat pad tumor growth model. The co-delivery of drug and the CSC specific inhibitor towards targeted cancer chemotherapeutics provides an insight into anticancer strategy with facile control and high efficacy.

Targeting tumor metastases: Drug delivery mechanisms and technologies

“…The most commonly applied approach has centered on hyaluronic acid (HA), which is a natural glycosaminoglycan and intrinsic ligand for CD44 expressed on many cancer stem cells. HA has been functionalized to a variety of nanoparticles and used to target and increase the effectiveness of drug delivery in mammary fat pad and lung metastasis models [64, 65]. Another common cancer stem cell marker is CD133, which does not have an easily utilized natural ligand.…”

A Forecast of Targeting Leukemia Stem Cells by Nanomedicine

“…HA incorporated nanocarriers can deliver traditional chemotherapeutic drugs, such as doxorubicin and cyclosporine, to successfully target CD44 expressing CSCs both in vitro and in vivo [75]. This Nanomedicine based CSC targeting strategies have achieved prolonged survival in multiple animal cancer models including AML [76,[100][101][102][103]. Antibody incorporated nanocarriers have also been used for CSC targeting.…”

A novel double-targeted nondrug delivery system for targeting cancer stem cells

“…3 Previous research has shown that HA coatings can selectively and specifically target and deliver drugs to CSCs. 20,21 Therefore, HA was conjugated to the PEG-PLGA NPs to improve their targeting property to the CSCs in this study.…”

“…NPs that were synthesized in recent studies, which were used to selectively target and deliver drugs specifically to CSCs, tend to be coated with HA, and they are often accompanied by good success rates. 20,21,48 Furthermore, previous studies showed that CD44 interacts with HA to reduce tumorigenicity and cancer cells' migration ability, which enhances the sensitivity of cancer cells to the drug. 49 Therefore, in our study, HA was conjugated to the PEG-PLGA NPs to improve CSC targeting, and our results demonstrated that HA-PEG-PLGA NPs are more likely to be taken up by the 4T1 breast CSCs than the other control groups.…”