Nanotherapies, finally (or perhaps)
October 12, 2008
George S. Mack
BioDecade
Even older low-tech drugs could be much more effective as new treatments if
targeted to only diseased cells at high dose levels without toxic spillover into
normal tissues. Targeting is essential for intense, concentrated drug delivery.
Biomedical engineer Robert Langer of MIT (Cambridge, Mass. USA) and former
student Omid Farokhzad now of Harvard Medical School are co-founders of
BIND Biosciences (Cambridge, Mass., USA) which is engineering
nanoparticles to deliver a variety of drugs to specific cells and tissues for
multiple indications, including cancers. The company will launch a phase 1 trial
next year for an undisclosed late stage metastatic oncology indication. BIND’s
technology platform combines both passive and active principles for delivery of
drug to the desired locations. Passive delivery of nanoparticles to newly forming
and hence leaky vasculature in tumor tissue allows drug-laden particles
ranging from 50 to 150 nm to escape capillaries through gaps between the
boundaries of endothelial cells. “The physics work out perfectly,” says
Farokhzad. “Those fenestrations are just large enough to accommodate the
particles into the tissue.” The active component of the system is enabled
through the selective engagement of nanoparticle surface ligands designed to
bind specific receptors which could be any differentially expressed epitope,
including sugars or proteins on a target cell surface, or in the extracellular
matrix. But the “blood-brain barrier” attributable to tight endothelial junctions
remains an obstacle in potential treatment of brain metastasis, which is on
Farokhzad’s high priority list. “We were not as lucky with the brain, but this is an
engineering problem, and we are working on that now,” he says. “We will
publish a paper soon on how we propose to engineer nanoparticles in a
specific way to treat brain metastases.”
The company has already developed ideas and strategies for payload delivery
that include small molecules, peptides, proteins and oligonucleotides, such as
siRNAs or antagomirs to inhibit microRNAs. One of the major hurdles to
success has been the issue of how the nanoparticle might avoid immune
system surveillance, but at the same time not be so invisible that it can’t be
recognized by its intended target. Part of the answer was to coat the particle with
polyethylene glycol which acts as the stealth moiety and which prevents uptake
by the reticuloendothelial system. The other part of the solution was to find the
correct densities of the targeting and stealth components and get them into
balance. “Getting the densities of these two things just right was the answer
and is the key,” says Langer. “That was one of the most challenging things, and
a lot work has gone into this solution.” (Ref 1)
Langer is also on the founding board of directors as well as the scientific
advisory board (SAB) of Tempo Pharmaceuticals (Cambridge, Mass., USA)
which was also co-founded by a former student, biomedical engineer Ram
Sasisekharan of MIT. Tempo is developing nanoparticles for delivery of anti-
angiogenic and chemotherapeutic agents that can be released in sequence
over measured periods of time for optimal efficacy. The calculation is that if the
oncologist uses an angiogenesis inhibitor systemically to cut off blood supply to
the tumor, a chemotherapy agent cannot subsequently reach the diseased
tissue to initiate apoptosis because its supply line is shut down. Furthermore,
depriving the tumor mass of its blood supply can trigger a buildup of hypoxia-
inducible factor-1α (HIF1-α), which is associated with increasing tumor
malignancy and chemotherapy drug resistance.
Accordingly, the theory of temporal drug release is to make a nanoparticle with
the anti-angiogenesis drug in the outer core and the chemotherapeutic portion
in the inner core. The physical properties of the particles are such that, like BIND’
s nanoparticles, they are small enough to escape from the capillary
neovasculature into tumor tissues, but at about 200 nm they are sufficiently
large to become ensnared. Once they are wedged in place securely, the outer
core releases its drug to shut down the blood supply which leaves the particles
in the tumor bed as a residue to release the cytotoxic inner core drug over time.
“The design is simple really,” he says. “We started with size because we
wanted the particle to be retained. Then, the outer shell had to be released with
the proper kinetics to target and kill the endothelial cells.” Tempo and
Sasisekharan are planning a first clinical trial for 2010.
Both companies have developed the capabilities to deliver multiple drugs that
could be very different in character—even to the point of carrying and releasing
hydrophilic and hydrophobic molecules in the same nanoparticle. Tempo and
BIND have different patent estates, and they will serve the different needs of
their pharma partners.
1. Gu, F., Zhang, L., Teply, B.A., Mann, N., Wang, A., Radovic-Moreno, A.F.,
Langer, R. & Farokhzad, O.C., Precise engineering of targeted nanoparticles by
using self-assembled biointegrated block copolymers. PNAS, 105 (7), 2586-
2591 (2008).
October 12, 2008
George S. Mack
BioDecade
Even older low-tech drugs could be much more effective as new treatments if
targeted to only diseased cells at high dose levels without toxic spillover into
normal tissues. Targeting is essential for intense, concentrated drug delivery.
Biomedical engineer Robert Langer of MIT (Cambridge, Mass. USA) and former
student Omid Farokhzad now of Harvard Medical School are co-founders of
BIND Biosciences (Cambridge, Mass., USA) which is engineering
nanoparticles to deliver a variety of drugs to specific cells and tissues for
multiple indications, including cancers. The company will launch a phase 1 trial
next year for an undisclosed late stage metastatic oncology indication. BIND’s
technology platform combines both passive and active principles for delivery of
drug to the desired locations. Passive delivery of nanoparticles to newly forming
and hence leaky vasculature in tumor tissue allows drug-laden particles
ranging from 50 to 150 nm to escape capillaries through gaps between the
boundaries of endothelial cells. “The physics work out perfectly,” says
Farokhzad. “Those fenestrations are just large enough to accommodate the
particles into the tissue.” The active component of the system is enabled
through the selective engagement of nanoparticle surface ligands designed to
bind specific receptors which could be any differentially expressed epitope,
including sugars or proteins on a target cell surface, or in the extracellular
matrix. But the “blood-brain barrier” attributable to tight endothelial junctions
remains an obstacle in potential treatment of brain metastasis, which is on
Farokhzad’s high priority list. “We were not as lucky with the brain, but this is an
engineering problem, and we are working on that now,” he says. “We will
publish a paper soon on how we propose to engineer nanoparticles in a
specific way to treat brain metastases.”
The company has already developed ideas and strategies for payload delivery
that include small molecules, peptides, proteins and oligonucleotides, such as
siRNAs or antagomirs to inhibit microRNAs. One of the major hurdles to
success has been the issue of how the nanoparticle might avoid immune
system surveillance, but at the same time not be so invisible that it can’t be
recognized by its intended target. Part of the answer was to coat the particle with
polyethylene glycol which acts as the stealth moiety and which prevents uptake
by the reticuloendothelial system. The other part of the solution was to find the
correct densities of the targeting and stealth components and get them into
balance. “Getting the densities of these two things just right was the answer
and is the key,” says Langer. “That was one of the most challenging things, and
a lot work has gone into this solution.” (Ref 1)
Langer is also on the founding board of directors as well as the scientific
advisory board (SAB) of Tempo Pharmaceuticals (Cambridge, Mass., USA)
which was also co-founded by a former student, biomedical engineer Ram
Sasisekharan of MIT. Tempo is developing nanoparticles for delivery of anti-
angiogenic and chemotherapeutic agents that can be released in sequence
over measured periods of time for optimal efficacy. The calculation is that if the
oncologist uses an angiogenesis inhibitor systemically to cut off blood supply to
the tumor, a chemotherapy agent cannot subsequently reach the diseased
tissue to initiate apoptosis because its supply line is shut down. Furthermore,
depriving the tumor mass of its blood supply can trigger a buildup of hypoxia-
inducible factor-1α (HIF1-α), which is associated with increasing tumor
malignancy and chemotherapy drug resistance.
Accordingly, the theory of temporal drug release is to make a nanoparticle with
the anti-angiogenesis drug in the outer core and the chemotherapeutic portion
in the inner core. The physical properties of the particles are such that, like BIND’
s nanoparticles, they are small enough to escape from the capillary
neovasculature into tumor tissues, but at about 200 nm they are sufficiently
large to become ensnared. Once they are wedged in place securely, the outer
core releases its drug to shut down the blood supply which leaves the particles
in the tumor bed as a residue to release the cytotoxic inner core drug over time.
“The design is simple really,” he says. “We started with size because we
wanted the particle to be retained. Then, the outer shell had to be released with
the proper kinetics to target and kill the endothelial cells.” Tempo and
Sasisekharan are planning a first clinical trial for 2010.
Both companies have developed the capabilities to deliver multiple drugs that
could be very different in character—even to the point of carrying and releasing
hydrophilic and hydrophobic molecules in the same nanoparticle. Tempo and
BIND have different patent estates, and they will serve the different needs of
their pharma partners.
1. Gu, F., Zhang, L., Teply, B.A., Mann, N., Wang, A., Radovic-Moreno, A.F.,
Langer, R. & Farokhzad, O.C., Precise engineering of targeted nanoparticles by
using self-assembled biointegrated block copolymers. PNAS, 105 (7), 2586-
2591 (2008).
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