Bifunctional Elastin-like Polypeptide Nanoparticles
Bind Rapamycin and Integrins and Suppress Tumor Growth in Vivo
Version 2 2017-10-12, 13:30
Version 1 2017-10-12, 13:21
Posted on 2017-10-12 - 13:30
Recombinant
protein–polymer scaffolds such as elastin-like
polypeptides (ELPs) offer drug-delivery opportunities including biocompatibility,
monodispersity, and multifunctionality. We recently reported that
the fusion of FK-506 binding protein 12 (FKBP) to an ELP nanoparticle
(FSI) increases rapamycin (Rapa) solubility, suppresses tumor growth
in breast cancer xenografts, and reduces side effects observed with
free-drug controls. This new report significantly advances this carrier
strategy by demonstrating the coassembly of two different ELP diblock
copolymers containing drug-loading and tumor-targeting domains. A
new ELP nanoparticle (ISR) was synthesized that includes the canonical
integrin-targeting ligand (Arg-Gly-Asp, RGD). FSI and ISR mixed in
a 1:1 molar ratio coassemble into bifunctional nanoparticles containing
both the FKBP domain for Rapa loading and the RGD ligand for integrin
binding. Coassembled nanoparticles were evaluated for bifunctionality
by performing in vitro cell-binding and drug-retention assays and
in vivo MDA-MB-468 breast tumor regression and tumor-accumulation
studies. The bifunctional nanoparticle demonstrated superior cell
target binding and similar drug retention to FSI; however, it enhanced
the formulation potency, such that tumor growth was suppressed at
a 3-fold lower dose compared to an untargeted FSI–Rapa control.
This data suggests that ELP-mediated scaffolds are useful tools for
generating multifunctional nanomedicines with potential activity in
cancer.
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Dhandhukia, Jugal
P.; Shi, Pu; Peddi, Santosh; Li, Zhe; Aluri, Suhaas; Ju, Yaping; et al. (2017). Bifunctional Elastin-like Polypeptide Nanoparticles
Bind Rapamycin and Integrins and Suppress Tumor Growth in Vivo. ACS Publications. Collection. https://doi.org/10.1021/acs.bioconjchem.7b00469
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AUTHORS (13)
JD
Jugal
P. Dhandhukia
PS
Pu Shi
SP
Santosh Peddi
ZL
Zhe Li
SA
Suhaas Aluri
YJ
Yaping Ju
DB
Dab Brill
WW
Wan Wang
SJ
Siti M. Janib
YL
Yi-An Lin
SL
Shuanglong Liu
HC
Honggang Cui
JM
J. Andrew MacKay
KEYWORDS
ISRRGDscaffoldcanonical integrin-targeting ligandtumor growthFSIFK -506 binding protein 12Suppress Tumor Growthbreast cancer xenograftscell target bindingbifunctionalvivo MDA-MB -468 breast tumor regressionBifunctional Elastin-like Polypeptide Nanoparticles Bind RapamycinELP nanoparticleFKBPELP diblock copolymers