Cancer is currently the
second leading cause of death in the United States. 85%
of cancer patients have solid tumors and 50% of those patients
die as a result of malignant disease. Although metastases
are often the ultimate cause of death, a critical failure
in therapy, ultimately leading to metastases, is due to
the lack of control of the primary tumor. Local control
of the tumor is particularly difficult in the cervix, colon,
ovarian, pancreas, and brain. There is hence an urgent and
currently unmet need to improve therapy of primary tumors.
The delivery of therapeutic
agents to solid tumors is a significant problem because
of transport barriers that limit the delivery of drug to
a tumor. A second problem in cancer therapy is that chemo-
and radio-therapeutic agents are typically toxic to healthy
cells as well as tumor cells, which leads to undesirable
side effects during anticancer therapy. In an attempt to
overcome these problems in cancer therapy, different types
of drug delivery systems have been developed that employ
macromolecules, vesicles, or particles as carriers for therapeutics.
In general, these systems seek to maximize localization
of the drug to the tumor while minimizing systemic toxicity.
Although some of these approaches have shown promise in
preclinical studies, there is significant room for improvement
in the design of drug targeting systems for cancer therapy.
The Chilkoti Group has
developed a new method to thermally target polymer-drug
conjugates to solid tumors by exploiting the phase transition-induced
aggregation of ELPs. We hypothesized that ELPs conjugated
to drugs would enable thermally targeted drug delivery to
solid tumors if they were designed to exhibit a Tt
between body temperature and that of a heated tumor. Our
approach extends the concept of using a soluble macromolecular
carrier for drug delivery by introducing an active targeting
element via focused heating of the tumor by a hyperthermia
applicator. By exploiting the phase transition of these
polymers, this method potentially combines the thermal targeting
of the polymer-drug conjugate with the established advantages
of polymeric carriers (e.g., EPR effect, increased plasma
half-life and a high loading capacity) and hyperthermia
(e.g., increased cytotoxicity and macromolecular extravasation).
In previous work,
we designed pseudo-random ELPs with a MW of ~60 kDa that
exhibit inverse transition behavior between 37-42 ºC
at micromolar concentration, a temperature range that is
approved for clinical hyperthermia in humans. These “first
generation” ELP carriers were systemically injected
into the bloodstream of nude mice bearing human tumors and
the accumulation of the ELP was quantified with and without
hyperthermia of the tumors (tumors heated to 41.5 ºC).
These in vivo studies on implanted tumors in nude mice demonstrated
that thermal targeting provides a 2-fold increase in tumor
localization compared to a thermally insensitive control
polypeptide [Cancer
Research 61: 1548-1554, 2001].
We observed aggregates of the thermally responsive ELP by
fluorescence videomicroscopy within the heated tumor microvasculature
but not in control experiments, which was the first demonstration,
to our knowledge, that the phase transition of the ELP carrier
can be thermally triggered in vivo. More recently, we have
observed that thermally cycling the tumor can further increase
the uptake of the ELP within the tumor by up to five-fold
compared to the same polypeptide without hyperthermia [unpublished
results], suggesting an entirely new mode of enhancing the
delivery of drugs to tumors by the repeated, pulsed application
of mild heat.
We have also quantified
the cellular uptake of a thermally responsive ELP as a function
of hyperthermia in three different tumor lines by flow cytometry,
and its subcellular distribution by confocal fluorescence
microscopy [Cancer
Research 61: 7163-7170, 2001].
We showed that uptake of a thermally responsive ELP in all
three tumor cells increased significantly as a function
of hyperthermia, primarily due to its hyperthermia-mediated
phase transition. Furthermore, using confocal fluorescence
microscopy we have shown that tumor cells internalize the
thermally sensitive ELP from their extracellular environment.
The enhanced uptake of a thermally active ELP by tumor cells
in response to hyperthermia suggests that ELPs are a promising
macromolecular carrier for thermally targeted delivery of
cancer therapeutics. In ongoing collaborative studies with
Mark
Dewhirst at the Duke University
Cancer Center, we are now examining the feasibility of using
ELP carriers to thermally target chemotherapeutic agents
(Doxorubicin and cyclophosphamides), to heated tumors [J.
Contr. Reel. 91: 31-43, 2003],
as well as the systemic delivery of radionuclides (Astatine-211)
in collaboration with Michael
Zalutsky
(Dept. Radiology, Duke University).
In the next five years
we plan to develop the next generation of stimulus responsive
ELP carriers for drug delivery. These ELP will be based
on a di-block ELP motif, where one of the two blocks will
be designed to undergo its phase transition between 37 and
42 ºC. In one design that we are currently working
on in my laboratory, ELP di-block polymers are being designed
that undergo a monomer-micelle transition at ~40ºC
for multivalent targeting of drugs and imaging agents to
the tumor endothelium. Another class of block copolymers
are being designed that undergo a micelle-aggregate transition
at ~40ºC, for thermally triggered release of encapsulated
drugs. Future plans also involve the incorporation of orthogonal
triggers (e.g., pH and protease sensitivity) for triggered
release of drugs from these nanocapsules.
