Cold responsive nanoparticles for overcoming cancer drug resistance
T2019-059 A cold-responsive nanoparticle that quickly disassembles upon ice cooling leading to intracellular burst release of a chemotherapeutic drug in seconds
Stimuli-responsive nanoparticles (NPs) hold great promise for controlling drug release inside cancer cells. An obstacle to the effectiveness of this approach to chemotherapeutic drug delivery is the rapid expulsion of the delivered drug catalyzed by efflux pumps in the cell's plasma membrane. Multidrug-resistant cells, such as cancer stem cells (CSCs), are characterized by overexpression of these transporter-based efflux pumps. While stimuli-responsive NPs may be taken up by cancer cells via endocytosis, most of these NPs, such as pH- or heat-responsive ones, slowly release their drug cargo over hours to days resulting in the slowly released drug being pumped out of the cells before binding with the drug target within the cell nucleus. This creates a need for for a rapid-release NP such that the quickly-released drug can bind with its target before efflux pump depletion.
Researchers at Ohio State University and the University of Maryland have developed a hybrid (phospholipid/polymer) nanoparticle that achieves burst-release of the encapsulated drug by quick, irreversible disassembly of the NP. This NP disassembly occurs with ice cooling, or via other cooling procedures, below about 12°C. This cooling also, of itself, compromises the pumping capacity of the membrane transporters. Under the cooled condition, binding of the drug, for example DOX, with its target within the cell nucleus is evident, while it is minimal in cells kept at 37°C. NP targeting of cancer cells is achieved by decorating the NP surface with hyaluronic acid because hyaluronic acid is the natural ligand of the variant CD44 commonly overexpressed on many types of cancer cells and particularly CSCs. The researchers have demonstrated effective killing of drug-resistant ovarian cancer cells and associated CSCs in vitro and have also demonstrated destruction of both subcutaneous and orthotopic ovarian tumors in vivo with no evident systemic toxicity.
- Cancer treatment
- Cold-triggered burst release of encapsulated drug (e.g. DOX); NPs irreversibly disassemble
- Drug release in seconds versus hours or days for other stimulus-responsive NPs
- Required release temperature well-tolerated by normal tissue/cells in application area
- Rapid drug release defeats ability of efflux pumps to efficiently pump drug out of cells prior to drug binding with target within cell nucleus
- Cold effect reduces membrane transporter activity, further supporting drug retention
- In vitro and in vivo studies demonstrate killing of ovarian cancer cells and destruction of ovarian tumors
- Demonstrated efficacy in cancer stem cells (CSC enriched spheres) as well as multi-drug resistant cells