Biomedical Engineering Reference
In-Depth Information
Cyc losporine A (CsA) is an immu nosuppress ive agent
that can be used orally to treat acute inflam matory skin
conditions. Systema tically, administrat ion of CsA showed
signs of toxi city and trial s with topical administ ration have
proven ineffective due to very low skin penet ration [116] .
Psorban
1
is a topical formulat ion for treatme nt of psorias is
developed by CellGate , where Cs A is linked to TAT that has
been proven effective in Phase II clinical studies. (For review
see [117]). Alopec ia areata is an autoimm une d isease that
causes hair loss [116]. It was specu lated that formulat ions
that are effective for psori asis mos t likely would be effective
in alopecia areata as well .
Ex cessive swe ating is a condition that can affect soci al
life and is treated by injecti ons of botulinu m toxin (Botox).
The method is time consumi ng, requiring as many as 120
injections to treat the palm of the hands. A possibl e new
therapeutic method has been pres ented by Revance Th er-
apeutics. RT001 is a topical gel whe re a botulinu m toxin
type A is fuse d to a CPP for treatme nt of excessive sweating,
but it has also been effective in treating wrinkles aroun d the
eyes, so cal led later al canth al lines or crow's feet wrinkles .
1
AZX 100 is a phospho rylated analog of the heat shock
protein 20, HSPA20, attac hed to the CPP named YARA
developed by Ca pstone
2
[118,1 19]. It is current ly in a Phase
II clini cal trial for inhi bition of dermal scarri ng.
AVI-5038 is a polyarginine and aminohexanoic,
(RXRRBR)2, based CPP conjugated to a PMO that has
been developed by AVI Biopharma for treatment of Duchenne
Muscular Dystrophy.
3
Clinical studies were planed to start in
February 2010, but signs of toxicity were seen in doses at
15 mg/kg and the clinical studies were discontinued [120,121].
are predo minantly found at higher conce ntrations in cance r
cells [10,134,135 ]. ACPPs linked to nanopa rticles togethe r
with the dyes Cy5 and/or gadol inium for imagi ng gave a
high uptake in tumor cells that was betwee n 4- and 15-f olds
higher than ACCPs [135]. The results indicate that this
techniq ue could be used in fluo rescence-gui ded surgery,
since stud ies have shown that tumors as small as 200
m
m
in diameter can be detected in animal studies and a sign ifi-
cantly lower residua l cancer cells [9,135 ]. Th e plasma h alf-
life was proven to be around 9 h, a major im provement from
the fre e ACPP, which have a plas ma half -life of
10 min
[135]. ACPPs have shown to be effective in cancer detect ion,
cancer imagi ng, and cancer treatme nt whe re norm al cells are
mostly unaffected, in contras t to present ly available cance r
treatme nt [9].
Substance P is a neuro peptide that has been modi fied by
Kossiakoff and colleagu es to selectively and efficient ly
transduce cells expressing the neurokinin-1 receptors
(NK1R) [136]. The NK1R is overexpressed in certain can-
cers, specifically brain tumors, and the tumor specificity
could be useful in cancer treatment [136]. The substance P
modified peptide conjugated to a synthetic antibody fragment
specifically internalized and accumulated in tumors, which
could be useful in imaging and cancer diagnosis [136].
<
26.6 CON CLUS IONS AND FUTU RE
PERSPE CTIVES
CPPs have enorm ous therapeutic pote ntial [137] . Intra-
cellular delivery med iated by CPPs need not be restricted
to protei ns alone. In addi tion to protei n transduc tion, CPPs
provide efficient mea ns for d elivery of various macrom o-
lecules. For example, delivery of cance r chemot herapeut ic
drugs and larger DNA construc ts coul d be enhanced.
Although many of the stud ies performed on CPP-fus ion
proteins aim at stud ying biologi cal mechanism s in vitro or
designi ng therape utic applications for use in vivo , ex v ivo
applications could also prove interesting. Stem cell expan-
sion through growth stimulation via intracellular delivery of
proteins such as SV40 large T antigen has been used as an
example of one such potential application [138,139].
It is not certain that the best way to introduce proteins to
cells using CPPs it to covalently couple them together.
Another method that has shown promising results in other
applications such as siRNA delivery is the coincubation
strategy. This is a method that does not require the use of
prokaryotic expression systems. Instead, this strategy uti-
lizes interactions based on the positive charge of CPPs and
negative charges in for example siRNA [140,141]. This
method has also been employed for delivery of proteins,
where the formation of stable complexes relied on hydro-
phobic interactions between the CPP Pep-1 and two different
proteins GFP and
b
-Gal; a transfection rate for both the
26.5 ALTE RNATI VES/ VARIA NTS OF THIS
APPRO ACH
Th e a b i lity o f C P P t o d e l iver ca rgo i s n o t lim ite d to
pr o t ei ns a n d s ever a l re p o r t s h ave p r ove n t h e a b ilit y o f
using CPPs to greatly enhance cell internalizat ion for
cargoes suc h a s nucleic acids, imaging a gents, nanopar-
ticles, liposom es, small pharmaceuti cal molecul es, DNA,
and p e pt ides .
In order to use CPPs as pharmac eutica ls, modifica tions
are needed to enhanc e speci ficity, and one interesting
approach is activatibl e cell-penet rating peptides (ACPP) .
ACPPs are polyc ationic cell-penetra ting peptide s covalently
bound to a polyanio nic domain, which inhibits cell intern al-
ization until the covale ntly binding is cleaved [10,13 4]. Th is
reported method is desi gned toward cancer ther apy where
the covalent binding is cleaved by metal loprotease s, which
1
http://www.revance.com, htpp://clinicalTrials.gov NCT00888914
2
http://www.capstonethx.com
3
http://www. aviobio.com
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