(575b) Nanoparticles for Combination Chemotherapy

Nanoparticles for
Combination Chemotherapy

Shani L. Levit,
Christina Tang

School
of Engineering, Department of Chemical and Life Sciences Engineering

            The effectiveness of chemotherapy
(e.g. paclitaxel) can decrease with continual use due to development of multi-drug
resistance (MDR). MDR results in an overexpression of ATP-binding cassette
(ABC) transporters, which remove the anti-cancer drugs from the tumor cells. ABC
transporter inhibitors, e.g. lapatinib, have be used in combination with chemotherapeutics
(e.g. paclitaxel) to overcome MDR.  Current
practices include sequential delivery of lapatinib followed by paclitaxel. However,
these drugs are poorly soluble in the blood and cause severe side effects,
limiting their efficacy. pH-responsive nanoparticles could facilitate controlled
drug release to increase drug efficacy while limiting side effects. One
approach to achieving pH responsive nanoparticles has been encapsulation of
anti-oxidant metal complexes using a block copolymer stabilizer via Flash
NanoPrecipitation (FNP).  In
FNP, an antioxidant, tannic acid (TA), dissolved with an amphiphilic PEG-based
block copolymer is rapidly mixed with Fe³⁺ (aq.).  Upon mixing at pH 7.4, TA and Fe³⁺
form insoluble complexes which are encapsulated and stabilized by the
amphiphilic block copolymer.  The
resulting nanoparticle is pH-responsive; the nanoparticles are stable under
basic conditions (pH >7) when the complex is insoluble and disassemble in acidic environments
(pH <2) when the complex is soluble. The
overall goal is to achieve controlled release of combinations chemotherapies.  In this work, we encapsulate weakly
hydrophobic drugs (i.e. paclitaxel, lapatinib, and sulfasalazine) using two
methods 1) direct encapsulation by dissolving the drugs with TA and the block
copolymer and 2) encapsulation of hydrophobic prodrugs. For example, particles encapsulating
paclitaxel 128 nm ± 3 nm in diameter have been achieved via direct
encapsulation. The encapsulation efficiency of paclitaxel was ~ 80%. The size
and encapsulation efficiency will be compared for single and co-loaded nanoparticles.
The effect of pH on drug release will be discussed.