Asialoglycoprotein receptor targeted delivery of doxorubicin nanoparticles for hepatocellular carcinoma.
We report asialoglycoprotein receptor (ASGPR)-targeted doxorubicin hydrochloride (Dox) nanoparticles (NPs) for hepatocellular carcinoma (HCC). Polyethylene sebacate (PES)-Gantrez® AN 119 Dox NPs of average size 220 nm with PDI < 0.62 and ∼20% Dox loading were prepared by modified nanoprecipitation. ASGPR ligands, pullulan (Pul), arabinogalactan (AGn), and the combination (Pul-AGn), were anchored by adsorption. Ligand anchoring enabled high liver uptake with a remarkable hepatocyte:nonparenchymal cell ratio of 85:15. Furthermore, Pul-AGn NPs exhibited an additive effect implying incredibly high hepatocyte accumulation. Galactose-mediated competitive inhibition confirmed ASGPR-mediated uptake of ligand-anchored NPs in HepG2 cell lines. Subacute toxicity in rats confirmed the safety of the NP groups. However, histopathological evaluation suggested mild renal toxicity of AGn. Pul NPs revealed sustained reduction in tumor volume in PLC/PRF/5 liver tumor-bearing Nod/Scid mice up to 46 days. Extensive tumor necrosis, reduced collagen content, reduction in the HCC biomarker serum α-fetoprotein (p < 0.05), a mitotic index of 1.135 (day 46), and tumor treated/tumor control (T/C) values of <0.42 signified superior efficacy of Pul NPs. Furthermore, weight gain in the NP groups, and no histopathological alterations indicated that they were well tolerated by the mice. The high efficacy coupled with greater safety portrayed Pul Dox NPs as a promising nanocarrier for improved therapy of HCC.
a Department of Pharmaceutical Sciences and Technology , Institute of Chemical Technology (Deemed University, Elite Status) , Mumbai , Maharashtra , India and.
Sandhya
S
Pranatharthiharan
a Department of Pharmaceutical Sciences and Technology , Institute of Chemical Technology (Deemed University, Elite Status) , Mumbai , Maharashtra , India and.
Mitesh D
MD
Patel
a Department of Pharmaceutical Sciences and Technology , Institute of Chemical Technology (Deemed University, Elite Status) , Mumbai , Maharashtra , India and.
Vinod C
VC
Malshe
b National Institute of Immunohaematology , Mumbai , Maharashtra , India.
Vaishali
V
Pujari
b National Institute of Immunohaematology , Mumbai , Maharashtra , India.
Ajit
A
Gorakshakar
b National Institute of Immunohaematology , Mumbai , Maharashtra , India.
Manisha
M
Madkaikar
b National Institute of Immunohaematology , Mumbai , Maharashtra , India.
Kanjaksha
K
Ghosh
a Department of Pharmaceutical Sciences and Technology , Institute of Chemical Technology (Deemed University, Elite Status) , Mumbai , Maharashtra , India and.
Padma V
PV
Devarajan
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage* / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity; D037263:Asialoglycoprotein Receptor / Q000378:metabolism*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D003094:Collagen / Q000378:metabolism; D004317:Doxorubicin / Q000008:administration & dosage* / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity; D004337:Drug Carriers; D004339:Drug Compounding; D005260:Female; D005685:Galactans / Q000737:chemistry / Q000378:metabolism; D005936:Glucans / Q000737:chemistry / Q000378:metabolism* / Q000633:toxicity; D056945:Hep G2 Cells; D006801:Humans; D008024:Ligands; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008938:Mitosis / Q000187:drug effects; D008940:Mitotic Index; D050997:Nanomedicine; D053758:Nanoparticles; D009336:Necrosis; D011091:Polyesters / Q000737:chemistry* / Q000633:toxicity; D017207:Rats, Sprague-Dawley; D013678:Technology, Pharmaceutical / Q000379:methods; D013997:Time Factors; D014018:Tissue Distribution; D059551:Toxicity Tests, Subacute; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays; D000509:alpha-Fetoproteins / Q000378:metabolism
C097353:AFP protein, human; D000903:Antibiotics, Antineoplastic; D037263:Asialoglycoprotein Receptor; D004337:Drug Carriers; D005685:Galactans; D005936:Glucans; D008024:Ligands; D011091:Polyesters; D000509:alpha-Fetoproteins; C546772:polyethylene sebacate; D004317:Doxorubicin; C009109:pullulan; D003094:Collagen; C005653:arabinogalactan
PLC/PRF/5 liver tumor; Pullulan; arabinogalactan; asialoglycoprotein receptor; doxorubicin hydrochloride; hepatocellular carcinoma