repair and proliferation. Exposure to trastuzumab is thought to suppress the protective effect of
neuregulins. Hence, the risk of cardiotoxicity caused by doxorubicin is amplified when used with
trastuzumab, as there the protective system is suppressed (Rayson, et al., 2008). A widely cited
clinical trial by Slamon, et al. first used this combination of drugs. Their result showed that a
significant proportion of the patient population developed major cardiotoxixity (27%), with 16%
patients experiencing Congestive Heart Failure (Slamon, et al., 2001).
Due to its systemic distribution, it is not always practical to administer free form doxorubicin in
cancer patients. Instead, advances in technology have allowed the use of liposomes to target the drug
to a specific tissue. A liposome is a type of nanoparticle. It is a closed spherical vesicle consisting of
at least one phospholipid bilayer (Allen, et a l., 2004). These vesicles can be used as vehicles for
various drugs.
Immunotargeting is used to target liposomes to specific tissues. Antibodies for certain surface
biomarkers of the targeted tissues are added to the liposome. Once the antibodies have attached
themselves to the antigen, the drug is released form the liposome. This allows reduced systemic
distribution of the drug, and the drug is instead concentrated to the targeted tissue (Ferrari, 2005)
A study by Schmeeda, et al. (2009) investigated the effect of HER-2 targeted Pegylated Liposomal
Doxorubicin (HT-PLD) on binding rate with HER-2 expressing cells. The study found that adding
anti HER-2 antibodies to PLDs improved their binding capacity to HER-2 expressing cells by more
than 10 times in vitro. Liposomal doxorubicin now manufactured worldwide since its recent approval
by the FDA.
Liposomes are generally rapidly cleared from the body’s bloodstream when administered
intravenously by the action of the body’s reticulo-endothelial system. Thus, they have a short
biological half-life.
Methods of increasing the circulation time of liposomes have been developed. One of the most
commonly used methods is surface modification of the liposomes by adding PEG molecules
(Polyethylene Glycol). The added PEG molecules tend to shield the liposome from interactions with
other macromolecules such as blood opsonins, and allow it to circumvent the reticulo-endothelial
system of our body (De Rose, et al., 2012 & Deshpande, et al., 2013). This greatly increases the time
period for which the liposome can circulate in the body.
With the development of liposomal doxorubicin, there is hope that this drug can be used with
trastuzumab for effective treatment of breast cancer. This combination is still in clinical trial phase,
and shows good hope for the future of chemotherapy. This review aims to examine some clinical trials
that have used this combination.
Study Purpose