Prolonged blood circulation and enhanced tumor accumulation of folate-targeted dendrimer-polymer hybrid nanoparticles.
Nanoparticle (NP)-based drug delivery platforms have received a great deal of attention over the past two decades for their potential in targeted cancer therapies. Despite the promises, passive targeting approaches utilizing relatively larger NPs (typically 50-200nm in diameter) allow for passive tumor accumulation, but hinder efficient intratumoral penetration. Conversely, smaller, actively targeted NPs (<20nm in diameter) penetrate well into the tumor mass, but are limited by their rapid systemic elimination. To overcome these limitations, we have designed a multi-scale hybrid NP platform that loads smaller poly(amidoamine) (PAMAM) dendrimers (~5nm in diameter) into larger poly(ethylene glycol)-b-poly(D,L-lactide) (PEG-PLA) NPs (~70nm). A biodistribution study in healthy mice revealed that the hybrid NPs circulated longer than free dendrimers and were mostly cleared by macrophages in the liver and spleen, similar to the in vivo behavior of PEG-PLA NPs. When injected intravenously into the BALB/c athymic nude mice bearing folate receptor (FR)-overexpressing KB xenograft, the targeted hybrid NPs encapsulating folate (FA)-targeted dendrimers achieved longer plasma circulation than free dendrimers and higher tumor concentrations than both free dendrimers and the empty PEG-PLA NPs. These results suggest that the hybrid NPs successfully combine the in vivo advantages of dendrimers and polymeric NPs, demonstrating their potential as a new, modular platform for drug delivery.
Department of Biopharmaceutical Sciences, University of Illinois, Chicago 60612, USA.
Suhair
S
Sunoqrot
Department of Biopharmaceutical Sciences, University of Illinois, Chicago 60612, USA.
Jason
J
Bugno
Department of Medicinal Chemistry and Pharmacognosy, University of Illinois, Chicago 60612, USA.
Daniel
D
Lantvit
Department of Biopharmaceutical Sciences, University of Illinois, Chicago 60612, USA; Department of Medicinal Chemistry and Pharmacognosy, University of Illinois, Chicago 60612, USA.
Joanna E
JE
Burdette
Department of Biopharmaceutical Sciences, University of Illinois, Chicago 60612, USA; Department of Biongineering, University of Illinois, Chicago 60612, USA. Electronic address: sphong@uic.edu.
Seungpyo
S
Hong
D000818:Animals; D045744:Cell Line, Tumor; D002626:Chemistry, Pharmaceutical; D050091:Dendrimers / Q000737:chemistry*; D004337:Drug Carriers; D005260:Female; D005492:Folic Acid / Q000097:blood* / Q000737:chemistry / Q000493:pharmacokinetics; D058972:Folic Acid Transporters / Q000378:metabolism; D006801:Humans; D007773:Lactates / Q000737:chemistry*; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D050997:Nanomedicine; D053758:Nanoparticles; D009369:Neoplasms / Q000378:metabolism*; D010316:Particle Size; D011092:Polyethylene Glycols / Q000737:chemistry*; D013678:Technology, Pharmaceutical / Q000379:methods; D014018:Tissue Distribution
D050091:Dendrimers; D004337:Drug Carriers; D058972:Folic Acid Transporters; D007773:Lactates; C104700:PAMAM Starburst; C088513:poly(lactic acid-ethylene glycol); D011092:Polyethylene Glycols; D005492:Folic Acid
Dendrimer; In vivo targeting; Nanoparticle