BY DEAN HO
Short drug circulation times and difficulty localizing therapy
to tumor sites are but two of the challenges associated
with existing cancer treatments. More troubling are
the issues of drug toxicity and tumor resistance. Toxicity can
cause major complications, such as low white-blood-cell counts
or heart fail ure, that necessitate cessation of treatment. The
tissue damage inflicted by some therapies can even be fatal.
And evolution of drug resistance by tumors accounts for the
vast majority of cases in which treatment fails. Given these and
other issues associated with treatment safety and efficacy, scientists
are applying tremendous effort toward the utilization of
nanomedicine in the fight against cancer.
Nanotechnology-based therapeutics have exhibited clear
benefits when compared with unmodified drugs, including
improved half-lives, retention, and targeting efficiency, and
fewer patient side effects. Researchers have already made progress
with chemotherapeutic nanomedicines in the clinic. Several
compounds that are in various stages of trials or already
approved by the U.S. Food and Drug Administration (FDA).
For example, Calando Pharmaceuticals has demonstrated the
first evidence of nanoparticle-delivered clinical RNA interference
(RNAi) (Nature, 464:1067-70, 2010). BIND Biosciences
has shown that nanoparticles combining a chemotherapeutic
drug with prostate-specific membrane antigen (PSMA) can
reduce lung and tonsillar lesions with greater efficacy compared
with the drug alone, and at substantially lower doses (Sci Transl
Med, doi:10.1126/scitranslmed.3003651, 2012). Furthermore
Celgene’s Abraxane, an albumin-functionalized paclitaxel formulation,
was initially approved by the FDA for sale as a breast
cancer therapy, but also recently received approval for the treatment
of lung and pancreatic cancers.
On the preclinical front, several nanomaterial formulations have
shown promise. Single-agent nanoparticle delivery, both actively and
passively targeted, has been demonstrated with a host of platforms
using silica, polymer, metal, and carbon-based materials.
Delivering a double whammy
Researchers recently reported multidrug delivery using nanoparticles
to mediate resistance in relapsing cancers and to improve
triple-negative breast cancer treatment efficacy. Other recent
approaches have included layer-by-layer siRNA and doxorubicin
delivery for breast cancer therapy, simultaneous loading of
small interfering RNA (siRNA) and tumor-penetrating peptides
against ovarian cancer, as well as sequential administration of multiple
types of nanoparticles for pancreatic cancer treatment (Adv
Funct Mater, doi:10.1002/adfm.201303222, 2014). These exciting
approaches have served as a foundation for the next phase of cancer
nanomedicine in the clinic—the rational design of nanomaterial-
drug combinations.
Until more nanoparticles are validated in the clinic, however,
the impact that nanomedicine may have on cancer treatment
has yet to be fully realized. In order for chemotherapies
modified using nanotechnology to profoundly change hematological
and oncological practice, the application of engineered
nanomedicines must be paired with emerging strategies to
rationally design nanotherapeutic combinations. This is critical
because combinatorial therapy is an efficient way to simultaneously
address the barriers to treatment success, and it is
widely used in treating cancer and infectious diseases.
Current clinical methodologies for combinatorial drug design
include additive treatments that combine two or more drugs
at their highest tolerable but still efficacious dose, although the
synergistic effects among drugs cannot be taken into account
using this additive approach. As the field gradually embraces the
use of nanoparticles to deliver multiple compounds with different
targets, a move away from additive dosing is necessary. This
raises several important questions. For example, silencing genes
to combat resistance, mediating apoptosis, and allowing vascular
access are each pathways worth targeting, but what if multiple
pathways are targeted at the same time to comprehensively
attack the tumor? How will dosing be determined? How will the
dosages of each drug be adjusted if efficacy is improved but toxicity
is worsened? More importantly, how will “optimization” be
defined, especially if the desired outcome is to simultaneously
stop tumor growth, eliminate resistance, maintain white blood
cell counts, and achieve a host of other objectives?
An attempt to optimize any one of these conditions will inevitably
affect the others. Furthermore, these conditions vary from
patient to patient, so phenotypic personalized medicine will be
required. In addition, these issues create a parameter space that
is too large to be individually tested and can result in an arbitrary
dosing scenario. For example, a combination of six candidate
therapeutics with 10 possible concentrations represents a minimum
of 1 million possible combinations. Identifying a solution
that rapidly converges on a defined set of phenotypic outcomes is
a challenge that faces both unmodified drug administration and
drug delivery by nanoparticles.
To move beyond short-term cancer management—or single
outcomes, like delaying tumor growth using a nanoparticle drug
formulation—and to enable long-term or potentially permanent
disease management, the field of nanomedicine will inevitably
need to be paired with advanced strategies to rapidly determine
dosing conditions that can simultaneously optimize for
efficacy and safety. One promising route is the field of feedback
system control (FSC), which relies on phenotypic responses
instead of trying to interrogate cellular pathways, their individual
protein components, or a spectrum of genotypic responses.
One example is the use of a search algorithm in a feedback loop
that can guide the formulation of rational drug combinations,
both unmodified and nanotherapeutic. (See PNAS, 105:5105-
10, 2008; BMC Systems Biology, 5:88, 2011.) Remarkably, this
approach can be used for in vitro studies with cell lines and primary
cells, and for preclinical and even clinical validation. And
because FSC utilizes outcomes to iteratively suggest new possible
combinations before rapid convergence—in tens of trials
versus a million or more—toward an optimal combinatorial
dose, pharmacokinetics and pharmacodynamics are inherently
accounted for with this approach. Furthermore, because combinations
will vary from patient to patient, FSC will help personalized
nanomedicine dosing on a case-by-case basis.
In sum, cancer nanomedicine possesses the versatility
required to uniquely overcome some of the most challenging
impediments to treatment success. Rationally designing
nanotherapeutic combinations using rapid convergence solutions
such as FSC represents a promising pathway from cancer
management towards cancer elimination.
Dean Ho is a professor of oral biology and medicine at
the University of California, Los Angeles (UCLA) School
of Dentistry, where he codirects the Weintraub Center for
Reconstructive Biotechnology. He is also a UCLA professor of
bioengineering and a member of the Jonsson Comprehensive
Cancer Center and California NanoSystems Institute.
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