ABSTRACT
The development of multidrug resistance (MDR) in cancer cells is of grave concern, limiting the
efficacy of anticancer agents and, hence, the failure of breast cancer therapy. Clinical research and
application revealed that in spite of its potential anticancer effects, doxorubicin is highly toxic, and its
long-term application may cause dose-dependent irreversible cardiomyopathy, severe cardiac
toxicity, or liver damage, thereby limiting its application in breast cancer treatment. Even if the drug
is super-efficient, if it still causes off-target toxicity and damages non-cancerous cells and tissues,
the drug wouldn’t be a great remedy to treat that particular disease. As such, the greater potential
of using doxorubicin as anticancer therapeutic depends on the availability of a targeted delivery
vehicle, which will not only enhance the killing of cancer cells but also minimize the off-target
toxicity to non-cancerous cells. The goal of this study is to enhance the delivery of doxorubicin
by formulating an aptamer-labeled liposomal nanoparticle delivery system that will carry and
deliver doxorubicin specifically into chemoresistant Her-2+ breast cancer cells. We have
recently reported that down regulating nuclear expression of MDR1 P-gp (ABCB1 gene) by P-gp
specific siRNA could increase the delivery of doxorubicin to doxorubicin resistant breast cancer cells.
However, since the Dox was delivered as a free drug solution without encapsulating it into a particle
for targeted delivery, it still caused toxicity to other non-cancerous cells. The targeted delivery of
siRNA to knockdown multi-drug resistant genes such as MDR1 P-gp, MRP or BCRP might be helpful
to circumvent MDR using the apt-labeled formulations that we have developed in our lab, however,
there are some questions that still need to be addressed (1) how can we deliver doxorubicin in a
more targeted fashion to the chemoresistant breast cancer cells so that the drug-enhanced
cytotoxicity to cancer cells increases with a minimal toxicity to the non-cancerous cells? We assume
that a targeted delivery system is an utmost requirement whether it is delivering siRNA to silence
chemoresistant genes or an actual chemodrug which will kill cancer cells without killing non-
cancerous cells. To address the chemoresistance as well as off-target toxicity, a targeted delivery
system for doxorubicin needs to be developed which should be innovative, comparable and can
minimize the toxicity to other non-cancerous cells. And (2) a strategy needs to be in place to
determine whether the targeted nanoparticles will carry both doxorubicin and siRNA within the same
particles or in different particles to get the best results preventing chemoresistance and limiting off-
target toxicity. Our hypothesis is that delivering doxorubicin and MDR-silencing siRNAs separately
by targeted nanoparticle system will enhance the cellular toxicity and antitumor effects as compared
to a targeted nanoparticle system that delivers the drug and siRNA simultaneously. This hypothesis
will be tested through two specific aims:
Aim 1: Targeted delivery of doxorubicin liposomes for Her-2 positive breast cancer treatment.
Aim 2: Assess whether the targeted nanoparticles will carry both doxorubicin and siRNA within the
same particles or in different particles to get the best results preventing chemoresistance and limiting
off-target toxicity.