Designing nanoparticles for selective targeting
PharmTech: Could you describe your research on nanoparticles as targeted drug delivery systems in the treatment of cancer?
Langer (MIT and BIND Biosciences): The idea of employing targeted nanoparticles to bring cancer drugs to the site of disease and increase their safety and effectiveness
has been around for several decades, but until recently the solution has been elusive. A major obstacle has been the inability
to achieve the optimal interplay of particle characteristics that confer targeting of diseased cells, evasion of particle
clearance mechanisms, and controlled release of the encapsulated drug payload.
In the mid 2000s, Omid Farokhzad at Harvard Medical School and I developed a new approach for targeting of drug-loaded polymeric
nanoparticles to disease sites, including cancer cells and diseased vasculature. The technology is based on a novel self-assembly
process which allows formation of nanoparticle libraries consisting of hundreds or even thousands of distinct nanoparticle
formulations. We developed methods to screen these particles to identify the ones with the optimal properties for diseased-tissue
targeting and avoidance of off-target tissues. Importantly, the particles we developed are composed of biocompatible and biodegradable
polymers that are commonly used in other pharmaceutical products such as biodegradable microspheres and PEGylated proteins.
Zale (BIND Biosciences): BIND is now using this platform to develop targeted nanoparticles called Accurins to treat cancer and other diseases. The
company has set about developing Accurins for clinical evaluation. The most advanced of these nanoparticles is BIND-014, an
Accurin targeted to a cell-surface receptor expressed in all major solid tumor types. BIND-014 contains the chemotherapeutic
agent docetaxel, which is a blockbuster drug in its own right, with approvals in five solid tumor indications, including breast,
lung, and prostate. BIND-014 has just completed a Phase I clinical trial and is advancing into Phase II. The early results
for BIND-014 are very promising. We have seen that the drug behaves very differently from conventional docetaxel, including
showing signs of activity at relatively low doses and in tumors where docetaxel is not normally used.
Zhao (NTU): Our multifunctional meso-porous silica nanoparticles for cancer-targeted and controlled drug delivery have three components—the
mesoporous silica nanoparticle core, the amino-β-cyclodextrin, the PEG polymers functionalized with an adamantane (Ad) unit
at one end and a folate (FA) unit at the other end (Ad-PEG-FA) (18). The surface of mesoporous silica nanoparticles is firstly
functionalized with amino-β-cyclodextrin rings bridged by cleavable disulfide bonds, blocking drugs inside the mesopores of
the nanoparticles. The Ad-PEG-FA polymers are immobilized onto the nanoparticle surface through strong -cyclodextrin/adamantane
complexation. The multifunctional nanoparticles can be efficiently trapped by folate-receptor-rich cancer cells through receptor-mediated
endocytosis, where they then rapidly release the loaded anticancer drug inside the cell when triggered by the acidic pH and
Several functions are built onto the multifunctional nanoparticles to deliver drugs in an optimal fashion. These functions
- PEGylated coating on the nanoparticle surface to enhance long-term stability of the nanoparticles under physiological conditions
- Active cancer targeting by the folate ligands attached onto the nanoparticle surface
- pH-triggered drug release to allow drug released within acidic intracellular compartments such as endosome and lysosome (pH
- Positively charged nanoparticle surface under acidic conditions to facilitate the transfer of the nanoparticles from endosome
- Glutathione-induced cleavage of the disulfide bonds to further enhance the drug release in the cytoplasm of cancer cells.
The engineering of these functions onto the single nanoparticle entities significantly enhances the efficacy of anticancer
drug delivery to cancer cells, while reducing the cytotoxic effects on healthy cells. In vivo experiments demonstrate that doxorubicin-loaded multifunctional mesoporous silica nanoparticles could effectively release
doxorubicin to tumor sites resulting in significant inhibition of the tumor growth.