A novel approach to deliver anticancer drugs to key cell types in tumors using a PDGF receptor-binding cyclic peptide containing carrier.
Tumor stromal cells have been recently recognized to contribute to tumor growth. Therefore, we hypothesized that delivery of anticancer drugs to these cells in addition to the tumor cells might treat cancer more effectively. Stromal cells abundantly expressed Platelet-Derived Growth Factor Receptor-beta (PDGFR-beta) in different human tumors as shown with immunohistochemistry. To achieve targeting through PDGFR-beta, we developed a carrier by modifying albumin with a PDGFR-beta recognizing cyclic peptide (pPB-HSA). pPB-HSA specifically bound to PDGFR-beta-expressing 3T3 fibroblasts, C26 and A2780 cancer cells in vitro. Subsequently, doxorubicin was conjugated to pPB-HSA through an acid-sensitive hydrazone linkage. In vitro, Dox-HSA-pPB was taken up by fibroblasts and tumor cells and a short exposure of the conjugate induced cell death in these cells. In vivo, the conjugate rapidly accumulated into PDGFR-beta expressing cells in C26 tumors. Treatment with Dox-HSA-pPB significantly reduced the C26 tumor growth in mice while free doxorubicin treated mice had lower response to the therapy. Furthermore, in contrast to free doxorubicin the conjugate did not induce loss in body weight. In conclusion, the present study reveals a novel approach to target key cell types in tumors through PDGFR-beta, which can be applied to enhance the therapeutic efficacy of anticancer drugs.
Prakash
Jai
J
Department of Pharmacokinetics, Toxicology and Targeting, Groningen Research Institute for Pharmacy, University of Groningen, The Netherlands. J.Prakash@rug.nl
de Jong
Edwin
E
Post
Eduard
E
Gouw
Annette S H
AS
Beljaars
Leonie
L
Poelstra
Klaas
K
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D004317:Doxorubicin / Q000494:pharmacology*; D005260:Female; D006801:Humans; D051379:Mice; D041681:NIH 3T3 Cells; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000473:pathology; D010456:Peptides, Cyclic / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000378:metabolism* / Q000502:physiology; D012709:Serum Albumin / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D017154:Stromal Cells / Q000187:drug effects / Q000378:metabolism*
D000903:Antibiotics, Antineoplastic; D010456:Peptides, Cyclic; D012709:Serum Albumin; D004317:Doxorubicin; D020797:Receptor, Platelet-Derived Growth Factor beta