Doxorubicin delivery by polyamidoamine dendrimer conjugation and photochemical internalization for cancer therapy.
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.
Lai
Ping-Shan
PS
Department of Chemistry and Center of Nanoscience and Nanotechnology, National Chung-Hsing University, Taichung, Taiwan.
Lou
Pei-Jen
PJ
Peng
Cheng-Liang
CL
Pai
Chin-Ling
CL
Yen
Wei-Nen
WN
Huang
Ming-Yi
MY
Young
Tai-Horng
TH
Shieh
Ming-Jium
MJ
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
D000577:Amides; D000903:Antibiotics, Antineoplastic; D050091:Dendrimers; D004337:Drug Carriers; D006835:Hydrazones; C104700:PAMAM Starburst; D011073:Polyamines; D004317:Doxorubicin