Targeted Nanoparticles Assembled via Complexation of Boronic-Acid-Containing Targeting Moieties to Diol-Containing Polymers
- Creators
- Han, Han
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Davis, Mark E.
Abstract
The delivery of therapeutics via nanoscaled vehicles for solid cancer treatment can be enhanced by the incorporation of a targeting capability. Here, we describe a new method for assembling a targeted nanoparticle that utilizes the reversible covalent complexation between boronic acids and diols to achieve a targeted nanoparticle for the delivery of the anticancer drug camptothecin (CPT). CPT is conjugated to a biocompatible, hydrophilic copolymer of mucic acid and PEG (MAP). When this polymer–drug conjugate is placed in water, it self-assembles into MAP–CPT nanoparticles of ca. 30 nm (diameter) and slightly negative zeta potential. The antibody Herceptin is attached to a boronic acid via a polyethylene glycol (PEG) spacer, and this boronic acid-containing targeting moiety is complexed with the diol-containing MAP to form a targeted MAP–CPT nanoparticle. The addition of Herceptin targeting agent to the MAP–CPT nanoparticles yields targeted MAP–CPT nanoparticles with increased nanoparticle size to ca. 40 nm (diameter). The main mechanisms of CPT release from MAP–CPT nanoparticles are found by in vitro analysis to be hydrolysis and nanoparticle disruption by fat. Cellular uptake of nanoparticles is enhanced by 70% compared to nontargeted version by the incorporation of a single Herceptin antibody targeting agent per nanoparticle. This single Herceptin antibody targeted MAP–CPT nanoparticle system carries ca. 60 CPT molecules per nanoparticle and shows prolonged plasma circulation with an elimination half-life of 21.2 h and AUC value of 2766 μg.h/mL at a 10 mg CPT/kg tail vein injection in mice.
Additional Information
© 2013 American Chemical Society. Received: December 4, 2012; Revised: March 1, 2013; Published: March 6, 2013. Published In Issue April 17, 2013. We thank Alasdair McDowall, David VanderVelde, and Leonard Medrano for assistance with cryo-EM imaging, NMR spectroscopy, and cell culture preparation respectively. This project was financially supported by the National Cancer Institute Grant CA 151819.Attached Files
Accepted Version - nihms453872.pdf
Supplemental Material - bc300640j_si_001.pdf
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Additional details
- PMCID
- PMC3656490
- Eprint ID
- 38663
- Resolver ID
- CaltechAUTHORS:20130523-162341580
- NIH
- CA 151819
- National Cancer Institute
- Created
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2013-05-24Created from EPrint's datestamp field
- Updated
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2021-11-09Created from EPrint's last_modified field