Journal
ACS APPLIED MATERIALS & INTERFACES
Volume 6, Issue 18, Pages 16416-16425Publisher
AMER CHEMICAL SOC
DOI: 10.1021/am504849x
Keywords
PAMAM dendrimers; lactobionic acid; PEG spacer; doxorubicin; targeted cancer therapy
Funding
- National Natural Science Foundation of China [21273032, 81341050]
- Ph.D. Programs Foundation of Ministry of Education of China [20130075110004]
- Science and Technology Collaboration Fund, Ministry of Science and Technology
- Program for Professor of Special Appointment (Eastern Scholar) at Shanghai Institutions of Higher Learning
- Fundacao para a Ciencia e a Tecnologia (FCT)
- Santander bank for the Invited Chair in Nanotechnology
- FCT [PTDC/CTM-NAN/1748/2012]
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We report the development of a lactobionic acid (LA)-modified multifunctional dendrimer-based carrier system for targeted therapy of liver cancer cells overexpressing asialoglycoprotein receptors. In this study, generation 5 (G5) poly(amidoamine) (PAMAM) dendrimers were sequentially modified with fluorescein isothiocyanate (FI) and LA (or polyethylene glycol (PEG)-linked LA, PEG-LA), followed by acetylation of the remaining dendrimer terminal amines. The synthesized G5.NHAc-FI-LA or G5.NHAc-FI-PEG-LA conjugates (NHAc denotes acetamide groups) were used to encapsulate a model anticancer drug doxorubicin (DOX). We show that both conjugates are able to encapsulate approximately 5.0 DOX molecules within each dendrimer and the formed dendrimer/DOX complexes are stable under different pH conditions and different aqueous media. The G5.NHAc-FI-PEG-LA conjugate appears to have a better cytocompatibility, enables a slightly faster DOX release rate, and displays better liver cancer cell targeting ability than the G5.NHAc-FI-LA conjugate without PEG under similar experimental conditions. Importantly, the developed G5.NHAc-FI-PEG-LA/DOX complexes are able to specifically inhibit the growth of the target cells with a better efficiency than the G5.NHAc-FI-LA/DOX complexes at a relatively high DOX concentration. Our results suggest a key role played by the PEG spacer that affords the dendrimer platform with enhanced targeting and therapeutic efficacy of cancer cells. The developed LA-modified multifunctional dendrimer conjugate with a PEG spacer may be used as a delivery system for targeted liver cancer therapy and offers new opportunities in the design of multifunctional drug carriers for targeted cancer therapy applications.
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