Tumor targeting using polyamidoamine dendrimer-cisplatin nanoparticles functionalized with diglycolamic acid and herceptin.
Polymer mediated drug delivery system represents a novel promising platform for tumor-targeting with reduced systemic side effects and improved chemotherapeutical efficacy. In this study, we report the preparation and characterization of herceptin targeted, diglycolamic acid (DGA) functionalized polyamidoamine (PAMAM) dendrimer as a potent drug carrier for cisplatin. DGA dendrimers carrying cisplatin demonstrated enhanced anticancer activity when targeted with herceptin. In vitro cell line studies with herceptin-DGA-G4-cisplatin in HER-2 +ve and HER-2 -ve human ovarian cancer cell lines showed that these nanoparticles possessed remarkable features such as lower IC50 value, improved S-phase arrest, and enhanced apoptosis due to increased cellular uptake and accumulation than the untargeted DGA-G4-cisplatin and free cisplatin. Furthermore, in vivo results in SCID mice bearing SKOV-3 tumor xenografts, herceptin-DGA-G4-cisplatin, appeared to be more effective in inducing tumor regression as compared to free cisplatin. Collectively, these results indicate that herceptin targeted DGA functionalized PAMAM-cisplatin conjugates serve as better anti-tumor agents than individual therapeutic agents.
Department of Human Genetics, Sri Ramachandra University, Chennai 600116, Tamil Nadu, India.
Akila
A
Kesavan
Radiological Safety Division, Indira Gandhi Center for Atomic Research, Kalpakkam 600102, Tamil Nadu, India.
P
P
Ilaiyaraja
Department of Human Genetics, Sri Ramachandra University, Chennai 600116, Tamil Nadu, India.
W
W
Sofi Beaula
Department of Biotechnology, Indian Institute of Technology, Madras, Chennai 600036, Tamil Nadu, India.
Vuttaradhi
V
Veena Kumari
Centre for Toxicology and Developmental Research, Sri Ramachandra University, Porur, Chennai 600116, Tamil Nadu, India.
J
J
Sugin Lal
Department of Biotechnology, Indian Institute of Technology, Madras, Chennai 600036, Tamil Nadu, India.
C
C
Arunkumar
Department of Human Genetics, Sri Ramachandra University, Chennai 600116, Tamil Nadu, India.
G
G
Anjana
Department of Radiotherapy, Sri Ramachandra Medical College & Research Institute, Chennai, Tamil Nadu, India.
Satish
S
Srinivas
Medical Oncology, Department of General Medicine, Sri Ramachandra Medical College & Research Institute, Chennai, Tamil Nadu, India.
Anita
A
Ramesh
Department of Biotechnology, Indian Institute of Technology, Madras, Chennai 600036, Tamil Nadu, India. Electronic address: rayala@iitm.ac.in.
Suresh Kumar
SK
Rayala
Safety Engineering Division, Indira Gandhi Center for Atomic Research, Kalpakkam 600102, Tamil Nadu, India. Electronic address: pon@igcar.gov.in.
D
D
Ponraju
Department of Human Genetics, Sri Ramachandra University, Chennai 600116, Tamil Nadu, India. Electronic address: ganeshv@sriramachandra.edu.in.
Ganesh
G
Venkatraman
D065567:Absorption, Physiological; D000081:Acetamides / Q000737:chemistry*; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000008:administration & dosage* / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D050091:Dendrimers / Q000737:chemistry*; D004339:Drug Compounding; D016503:Drug Delivery Systems; D005079:Excipients / Q000737:chemistry; D005260:Female; D006801:Humans; D020128:Inhibitory Concentration 50; D016513:Mice, SCID; D053758:Nanoparticles / Q000737:chemistry* / Q000648:ultrastructure; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D011897:Random Allocation; D016196:S Phase / Q000187:drug effects; D013499:Surface Properties; D000068878:Trastuzumab / Q000737:chemistry*; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
D000081:Acetamides; D000970:Antineoplastic Agents; D050091:Dendrimers; D005079:Excipients; C104700:PAMAM Starburst; D000068878:Trastuzumab; D002945:Cisplatin
Anti-tumor activity; Apoptosis; Cisplatin; Diglycolamic acid; Herceptin; PAMAM dendrimers; Targeted drug delivery