Building in optimal properties
PharmTech: What are the key considerations when designing nanoparticles for the delivery of cancer therapeutics? How do you engineer
these nanoparticles to achieve targeted delivery?
Zale (BIND Biosciences): This is a complicated question because the effects of many characteristics on how nanoparticles behave in the human body are
interdependent on one another. Broadly speaking though, for nanoparticles to be effective, they must be able to circulate
in the bloodstream, extravasate into diseased tissues, and release their therapeutic payload at a rate that provides high
concentrations at the target site.
We use particles based on copolymers of polylactic acid (PLA) or copolylactic/glycolic acid (PLGA) and PEG, and attach targeting
ligands to the end of the PEG chain. We have developed a particle-manufacturing process that encapsulates the drug payload
in the PLA/PLGA core of the particle and orients the PEG and the targeting ligand toward the surface of the particle. PEG
gives the particle a water-like corona, which disguises the particle from the systems in the body that would otherwise remove
them from the bloodstream within minutes after administration. As a result, our nanoparticles display circulation half-lives
of nearly 24 hours and are able to concentrate drugs in tumors at levels typically 10 times greater than when the same dose
is given as a solution.
Langer (MIT and BIND Biosciences): We have used a broad range of targeting ligands, including antibodies, antibody fragments, aptamers, peptides, and small molecules.
We have studied a range of targets including, for example, well-established and clinically validated tumor targets such as
the prostate-specific membrane antigen (PSMA) and human epidermal growth factor receptor 2 (HER2), and have discovered our
own targets and ligands in areas such as cardiovascular disease. At BIND, rapid clinical translation is important, and therefore,
the focus is on validated targets in areas of unmet clinical need such as cancer, and primarily using peptide and small-molecule
ligands for targeting.
There are many antigens or receptors expressed by cancer cells or the surrounding tissue that can be targeted by peptide and
small-molecule ligands, which are inherently more stable and less complex than macromolecular ligands such as antibodies and
aptamers. For examle, while our initial studies employed an aptamer that targets PSMA, BIND switched to a PSMA-binding small
molecule in BIND-014, which enabled them to quickly move into clinical development with a simple, pharmaceutically stable,
and well-characterized targeted particle. This PSMA-targeted particle can be manufactured reproducibly at large scale and
has been shown to be nontoxic in animal studies.
Zhao (NTU): Nanoparticles tend to aggregate as a result of their large surface-to-volume ratio in biological media. When nanoparticles
agglo-merate, they not only lose their intended functionality, but are quickly recognized and effectively removed by the mononuclear
phagocytic cells in the reticuloendothelial system (RES) of the liver and spleen. This sequestration is often increased by
the surface coating of nanoparticles with a corona of proteins that leads to opsonization and enhanced phagocytosis by the
A strategy to maintain good dispersion of drug-loaded nanoparticles in biological media is by surface modifications with PEG
polymers. PEG has been known to prevent protein adsorption (opsonization) on the nanoparticle surfaces, enhance circulation
time, reduce nonspecific RES uptake, and facilitate preferential accumulation at tumor sites through the EPR effect. Passive
targeting in itself, however, is often not enough to eradicate the side effects of cytotoxic drugs and divert the anticancer
therapy away from healthy cells to selectively target cancer cells.
To further enhance the targeting ability of drug-loaded nanoparticles, these systems must also be coupled with targeting agents
that can actively bind to over-expressed antigens or receptors on the surface of cancer cells. Drug-loaded nanoparticles can
be engineered to recognize and bind to cancer cells through ligand-receptor interactions and the bound nanoparticles are internalized
before the loaded drug is released inside the cells. Finally, there is another concern that these drug-delivery systems should
release the loaded drug rapidly upon accumulating at tumor sites and after being taken up by cancer cells.