Page 14 - Read Online

(Velcade , PS-341) was approved by the FDA in 2003 for et al. [101] demonstrated that their targeted nanoparticles
®
use against multiple myeloma, followed by Temsirolimus induced a significant tumor volume reduction compared
(Torisel , CCI-779), approved in 2007 for use against to untreated control and non-targeted groups in an in vivo
®
renal cell carcinoma. The majority of the other drugs -- MDA-MB 231 xenograft tumor model by developing
including Perifosine, 2-methoxyestradiol, Echinomycin, paclitaxel-loaded polymeric PLGA nanoparticles
Geldanamycin -- were terminated in either phase I or II conjugated with CD133 mAb. In another study done by
trials when they failed to show significant advantages. [89] Dou et al., [94] myeloma CSCs were treated with silver
nanoparticles decorated with anti-ABCG2 antibodies on
Lastly, targeting tumor vasculature is another way to the surface along with vincristine. Despite these advances
disrupt the CSC niche. Several agents blocking the in the laboratory, targeted nanoparticle approaches in the
activity of vascular endothelial growth factor, which CSC field are still in the early preclinical development
drives the migration of endothelial cells and stimulates stage due to limitations such as potential systemic
angiogenesis, are being tested in initial phases of toxicity, unwanted side effects, and poor extravasation
clinical therapy with moderate success. These include and exposure to their targets. [97,98,102]
Bevacizumab (Avastin ), Cediranib (AZD2171),
®
Sunitinib and Vandetanib. [82,90-93] It has been shown that using a CSC-targeted inhibitor
alone is not very effective in reducing the tumor bulk due
NANOMEDICINE IN COMBINATION to the fact that these inhibitors are not highly cytotoxic
THERAPY as compared with conventional chemotherapeutics.
Thereby, dual targeting nanoparticles loaded with CSC
Frequently after treatment, surviving CSCs induce inhibitors and conventional cytotoxic agents can improve
new tumor formation and metastases in which cancer clinical outcomes by effectively eradicating both CSCs
reappears in an even more aggressive form. With this and bulk tumor cells at the same time. When compared
phenomenon in mind, an increasing number of CSC- with the free drugs, the nanoparticle formulated drugs
targeted therapeutic agents have been developed over were significantly more effective and less toxic both in
the past several years such as salinomycin, curcumin, vitro and in vivo. [103-105]
thioridazine hydrochloride, sulforaphane, miR-34a,
and miR-130b. [94-97] Despite their therapeutic potential CONCLUSION AND FUTURE
in targeting CSCs, their clinical application has been PERSPECTIVES
hindered by their hydrophobicity, poor specificity and
poor pharmacokinetics (PK) profiles. [98-100] It is clear now that conventional chemotherapy is not
enough to overcome the abilities of CSCs to self-renew
Recent developments in nanoparticle delivery systems have and metastasize. A combination of surface markers and
provided new strategies to efficiently deliver therapeutics their functional properties have been used to identify
that can overcome the challenges posed by CSCs and and isolate CSCs. Despite this progress, there is still a
improve therapeutic efficacy of CSC-targeting agents by lack of reliable and accurate CSC markers. This must be
controlling release kinetics, prolonging circulation time overcome in order to develop therapeutic strategies with
and improving bio-distribution. In a study by Zhou et higher specificity and fewer side effects.
al., they used HPMA polymeric nanoparticles to deliver
[98]
a Hedgehog pathway inhibitor that efficiently eliminated Using either small molecule inhibitors or RNAi to target
CD133 cells within prostate tumors. Mamada and CSC-associated oncogenes and signaling pathways have
+
coworkers designed mesoporous silica nanoparticles to resulted in decreased functionality and numbers of CSCs
deliver a potent inhibitor of the Notch signaling pathway. and tumor regression in several pre-clinical models. CSCs
Their nanoparticle drug treatments efficiently targeted develop resistance to conventional chemotherapeutics,
CSC populations in the tumor. Furthermore, in the study but targeting ABC transporters resensitizes CSCs to
done by Wei and colleagues, salinomycin was conjugated those same drugs. Several studies have shown greater
to a hyaluronic acid-based nanogel to target CD44 drug CSC targeting effects by employing antibodies against
+
resistant cells which enhanced the therapeutic efficacy of CSC-specific biomarkers. Anti-CSC approaches such as
salinomycin. [97,98] CD44 and EpCAM antibodies could selectively induce
differentiation and inhibit proliferation.
Another advantage of using nanoparticles is the
additional capability to modify their surfaces with Modulating the immune system and tumor
targeting agents such as mAbs and peptides. High target microenvironment as a means of targeting CSCs has
selectivity and internalization can be achieved by surface shown encouraging results. However, the efficacy of
modification of nanoparticles with targeting moieties. As immunotherapy alone may be inadequate to produce clinical
previously discussed, CSCs are characterized by certain results. Therefore, combination therapy with conventional
surface markers; this allows specific targeting of CSCs modalities as well as with immunomodulatory agents may
as a therapeutic strategy for drug delivery. Swaminathan be of future interest to enhance therapeutic effects.
238
Journal of Cancer Metastasis and Treatment ¦ Volume 2 ¦ July 8, 2016 ¦