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Antitumor effects of an antibody (cetuximab)-targeted nanoparticle containing siRNA against EGFR

Pan, Dorothy W. and Davis, Mark E. (2014) Antitumor effects of an antibody (cetuximab)-targeted nanoparticle containing siRNA against EGFR. Cancer Research, 74 (19 Suppleme). Art. No. 4571. ISSN 0008-5472. http://resolver.caltech.edu/CaltechAUTHORS:20150604-145539780

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Abstract

Objective: Effective therapies for lung cancer that have mutated EGFR remain elusive. Because of the success of antibody-drug-conjugates, we are exploring the use of antibody targeted nanoparticles (NP) containing siRNA to produce multifunctional therapeutics. Here, we investigate the use of cetuximab (CTX) (commercial antibody to EGFR) targeted NPs containing siRNA against EGFR (sequence is for a region of the mRNA conserved in all types of mutations) in H1975 NSCLC xenografts. Methods: We synthesized a cationic mucic acid polymer by polymerizing a derivative of mucic acid, mucic acid ethylenediamine, with dimethyl suberimidate. This polycation can self-assemble with siRNA to form the NP. A methoxy polyethylene glycol (PEG) was modified to have a 5-nitrophenyl boronic acid (5-nPBA) moiety at one end to attach to diol groups on mucic acid and stabilize the NP. 5-nPBA-PEG with a carboxylic acid end group was conjugated to CTX to target the NP to EGFR receptors on the surface of cancer cells. These polymers were mixed with siRNA to form NPs, characterized by dynamic light scattering and cryo-transmission electron microscopy for size, and zeta potential measurements for surface charge. The NP was tested in vivo against tumors grown with H1975 NSCLC cells that contain the L858R and T790M mutations. NPs dosed iv (tail vein) at 9.3 mg/kg CTX targeting agent and 5 mg/kg siEGFR were injected twice a week for two weeks into nude mice with H1975 NSCLC xenografts and the anti-tumor effects compared to 9.3 mg/kg CTX (dosed iv tail vein) alone. Results: The CTX-targeted cMAP-siRNA NPs are ca. 40 nm in diameter as determined by both dynamic light scattering and cryo-TEM. The NPs' surface charge is slightly negative at -3.5 mV in 10 mM phosphate buffered at pH 7.4 (surrogate for extracellular conditions in vivo). When the NPs are in 1 mM KCl at pH 5.5 (surrogate for intracellular, endocytosis localization), the NP zeta potential is +1 mV indicating detachment of 5-nPBA-PEG from the NP at acidic pH. Thus, the NP is stabilized and targeted until it is endocytosed, where it disassembles to release the siRNA payload. We confirmed delivery of siEGFR to the tumor following two NP doses via a real-time PCR assay. In contrast to CTX treated mice that showed tumor growth delay but ultimately had tumors that grew to over 1000 mm^3, NP treated mice had tumors that remained below 200 mm^3 53 days following completion of 4 doses. Conclusions: NPs containing full antibodies as targeting agents and siRNA payloads can be formulated into well defined, stable experimental therapeutics. The NP system used here has a pH-tunable 5-nPBA that allows for targeting and stabilizing the NP at a physiologic pH of 7.4. The targeting agent and PEG coating is able to detach from the NP at acidic pH like those found in endosomes, enabling the siRNA payload to escape and reach its site of action within the cell. These NPs produce significant tumor regression in vivo that is superior to CTX alone.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1158/1538-7445.AM2014-4571DOIArticle
http://cancerres.aacrjournals.org/content/74/19_Supplement/4571PublisherArticle
Additional Information:©2014 American Association for Cancer Research.
Record Number:CaltechAUTHORS:20150604-145539780
Persistent URL:http://resolver.caltech.edu/CaltechAUTHORS:20150604-145539780
Official Citation:Dorothy W. Pan, Mark E. Davis. Antitumor effects of an antibody (cetuximab)-targeted nanoparticle containing siRNA against EGFR. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4571. doi:10.1158/1538-7445.AM2014-4571
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:58016
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:05 Jun 2015 03:40
Last Modified:05 Jun 2015 03:40

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