title: Doxorubicin delivery by polyamidoamine dendrimer conjugation and photochemical internalization for cancer therapy.
abstract: Coupling anticancer drugs to synthetic polymers is a promising approach to improve the efficacy and reduce the side effects of these drugs. The pH-activated polymer has been demonstrated to be a successful drug delivery vehicle system, whereas the photochemical internalization (PCI) was invented for site-specific delivery of membrane impermeable macromolecules from endocytic vesicles into the cytosol. In this study, doxorubicin (DOX) was conjugated to polyamidoamine (PAMAM) dendrimers via pH-sensitive and -insensitive linkers and was combined with different PCI strategies to evaluate the cytotoxic effects. Our results showed that both PCI strategies significantly improved the cytotoxicity of free DOX on Ca9-22 cells at higher concentrations. The 'light after' PCI treatment was efficient in releasing DOX from the PAMAM-hyd-DOX conjugates, resulted in more nuclear accumulation of DOX and more cell death through synergistic effects. On the other hand, antagonism was observed when 'light before' PCI combined with PAMAM-hyd-DOX conjugate. The distribution of PAMAM-amide-DOX was mainly cytosolic with or without PCI treatments. Both PCI strategies failed to improve the cytotoxicity of PAMAM-amide-DOX conjugates. Our results provide invaluable information in the future design of drug-polymer complexes for multi-modality cancer treatments.
authors.affiliation: Department of Chemistry and Center of Nanoscience and Nanotechnology, National Chung-Hsing University, Taichung, Taiwan.
authors.forename: Ping-Shan
authors.initials: PS
authors.lastname: Lai
authors.forename: Pei-Jen
authors.initials: PJ
authors.lastname: Lou
authors.forename: Cheng-Liang
authors.initials: CL
authors.lastname: Peng
authors.forename: Chin-Ling
authors.initials: CL
authors.lastname: Pai
authors.forename: Wei-Nen
authors.initials: WN
authors.lastname: Yen
authors.forename: Ming-Yi
authors.initials: MY
authors.lastname: Huang
authors.forename: Tai-Horng
authors.initials: TH
authors.lastname: Young
authors.forename: Ming-Jium
authors.initials: MJ
authors.lastname: Shieh
mesh_terms: D000577:Amides / Q000737:chemistry; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D045744:Cell Line, Tumor; D050091:Dendrimers; D004317:Doxorubicin / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D004337:Drug Carriers / Q000737:chemistry; D005887:Gingival Neoplasms / Q000188:drug therapy / Q000378:metabolism; D006801:Humans; D006835:Hydrazones / Q000737:chemistry; D006863:Hydrogen-Ion Concentration; D010777:Photochemistry; D011073:Polyamines / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics
chemical_list: D000577:Amides; D000903:Antibiotics, Antineoplastic; D050091:Dendrimers; D004337:Drug Carriers; D006835:Hydrazones; C104700:PAMAM Starburst; D011073:Polyamines; D004317:Doxorubicin