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Editorial
Paclitaxel Delivery Systems; From A
Stubborn Undruggable To an Efficient
Chemotherapeutic In Clinic
SM Journal
of Clinical
Pharmaceutica
Acta
Farid A. Dorkoosh1,2*, Pouya Dehghankelishadi1, 2 and Shabnam Samimi1, 2
1
2
Article Information
Received date: Nov 09, 2015
Accepted date: Nov 10, 2015
Published date: Nov 10, 2015
*Corresponding author
Farid A. Dorkoosh, Tehran University of
Medical Sciences, Iran, Tel/Fax: +098 21
88009440; Email: [email protected]
Distributed under Creative Commons
CC-BY 4.0
Department of Pharmaceutics, Faculty of Pharmacy, Tehran University of Medical Sciences, Iran
Medical Biomaterials Research Center, Tehran University of Medical Sciences, Iran
Excessive proliferation of cancer cells could be inhibited by disruption of microtubule
network. Paclitaxel (PTX), a well-known chemotherapeutics, stabilizes microtubule networks and
consequently interferes cell division. As other chemotherapeutics, pharmacodynamics of PTX
seems to be promising. However, the pharmacokinetics of PTX is a bottleneck of PTX formulation
development. Due to intrinsic hydrophobicity and instability in biological media, PTX is categorized
as an undruggable molecule. Another complication in clinical administration of PTX is off-target
effect and its side effects everywhere in the body. Furthermore, efflux-mediated drug resistance
diminish tiny amount of PTX reached to the tumor cells. Drug Delivery Systems (DDS) are unique
opportunity to transfer PTX formulations from test tubes to bed sides. This editorial focuses on the
role of PTX DDSs on solubilization, tumor targeting and overcoming drug resistance.
PTX as other Taxanes suffers from low solubility in biological media. In commercial formulation
of PTX, Cremophor EL is used as a co-solvent. Nevertheless, nephrotoxicity and hypersensitivity
reactions limited Cremophor based formulations. Genexol-PM is a micellar based formulation
which significantly increases the solubility by incorporation of PTX in hydrophobic core of micelle
while hydrophilic shell interacts with biological media [1]. Recently an aromatic methacrylamide
micelle is developed and evaluated [2]. In this study PTX content is stabilized within core of micelles
via interactions with aromatic groups. In addition, biodistribution studies have proven the enhanced
pharmacokinetics and tumor accumulation. In another study, PTX conjugated to chimeric peptides
which spontaneously form self-assembled nanoparticles, improved the aqueous solubility and
consequently tackled sub-optimal pharmacokinetics of PTX [3].
Off-target effect is another obstacle upon efficacy of PTX in clinic. Unwanted side effects
exacerbate patient’s condition and reduce compliance during chemotherapy period. DDSs could
passively and actively deliver PTX payload to cancer cells. Enhanced permeability and retention
effect (EPR) leads to accumulation of PTX drug delivery systems (PTX DDSs) to ravenous cancer
cells due to anomalous-leaky vascular network of tumor tissue [4].It is also reported in literature
that tumor priming with PTX DDSs modify tumor blood vessel pattern which leads to enhanced
EPR effect [5]. So PTX DDSs could be both cause and effect of EPR phenomenon. Abrexane,
albumin conjugated PTX, actively delivers cytotoxic payload to the target cancer cells [6]. Albumin
conjugates demonstrated a promising therapeutic outcome while minimizing unwanted side effect.
Decoration of DDSs with targeting moieties is another alternative for guiding PTX payload to its
target. Targeting can be achieved in several levels; tissue targeting, cell targeting and sub cellular
targeting. Our research groups have developed a hyaluronic acid coated micellar system which
actively targets CD-44 markers over expressed on tumor tissue [7, 8]. The next level is targeting
specific cell populations within tumor tissue. PLGA nanoparticles conjugated with anti CD-133
monoclonal antibodies target PTX to cancer stem cells [9]. Targeting specific cell population is not
the end for adventure of DDSs, It is start of another challenge; sub cellular targeting. Functionalized
liposomes with triphenylphosphonium (TPP) could be used for mitochondrial delivery [10].
Multidrug resistance (MDR) is another serious drawback in clinical efficacy of PTX. PTX is a
suitable substrate for p-glycoprotein (P-gp) thus maintaining optimal intracellular levels of PTX
is challenging. Co-administration of PTX along with efflux pump inhibitors using DDS platforms
has attracted the attention of many scientists. However, serious drug interaction and unfavorable
kinetics limited the administration of efflux pump inhibiters. So our research group focused on
innovative efflux pump inhibitors such as Lapatinib (LPT, a tyrosin kinase inhibitor). LPT block
HER-2 related signaling pathway while potentiating the effect of other chemotherapeutics via P-gp
inhibition as well. PTX-LPT loaded micelles and PTX-LPT loaded liposome are two combined
formulation which are developed for simultaneous delivery [11, 12]. Pluronic based delivery
system is another alternative for conquering MDR cells and sensitizing them to PTX [13]. Pluronic
destabilizes mitochondrial membrane which leads to ATP depletion and triggering intrinsic
OPEN ACCESS
How to cite this article Dorkoosh FA, Dehghankelishadi P and Samimi S. Paclitaxel Delivery Systems; From A Stubborn
Undruggable To an Efficient Chemotherapeutic In Clinic. SM J clin Pharm Acta. 2015;1(1):1002.
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apoptosis pathways within targets cells. As suggested in the literature,
aforementioned ATP depletion diminishes efflux mediated drug
resistance. Delivery of MDR-1 siRNA is another solution to MDR
challenge [14]. The studies have demonstrated in vitro and in vivo
efficacy of siRNA systems to sensitize resistant cells.
The emersion of PTX DDSs aroused a widespread optimism but
serious challenges are ahead. PTX DDSs are instable in biological
media due to rapid opsonization by Reticulo-Endothelial System
(RES). Furthermore pharmacokinetics and cellular uptake of
DDSs could be delayed by formation of protein corona. So more
profound studies on PTX DDSs interaction with biological surfaces
are required to ensure the clinic efficacy of these systems. Unless
extensive breakthroughs in targeting PTX payload to cancer cells,
still serious side effects are observed during clinical trials. Exploring
more specific targets and more selective targeting moieties are crucial
in designing the next generation of PTX DDSs. Scale up of PTX
DDSs and analogous nano platforms seems to be troublesome due
to their complex design. Development of robust preparation and
analytical methods to minimize batch to batch variation are required.
In some cases, PTX DDSs look like a Christmas tree full of useless
ornamentations. So we should keep in mind, for transferring PTX
DDSs from lab bench to patient’s bedside, it is necessary keeping
formulation design simple.
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Citation: Dorkoosh FA, Dehghankelishadi P and Samimi S. Paclitaxel Delivery Systems; From A Stubborn Undruggable To an
Efficient Chemotherapeutic In Clinic. SM J clin Pharm Acta. 2015;1(1):1002.
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