Importance of Avidity for an Endogenous Drug Carrier: An Antibody Carrier for CpG Oligonucleotides

• Published in: Molecular pharmaceutics Vol. 7; no. 4; pp. 1338 - 1341
• Main Authors: Cheung, Roland, Cho, Moo
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 02.08.2010
• Subjects: Animals; Antibodies - administration & dosage; Antibodies - chemistry; Antibodies - immunology; Cell Line, Tumor; Drug Carriers - administration & dosage; Drug Carriers - chemistry; Enzyme-Linked Immunosorbent Assay; Mice; Mice, Inbred BALB C; Neoplasms - drug therapy; Nitrobenzenes - chemistry; Oligodeoxyribonucleotides - administration & dosage; Oligodeoxyribonucleotides - chemistry; Oligodeoxyribonucleotides - immunology; avidity; Endogenous carriers; CpG ODN; pharmacokinetic and pharmacodynamic; immune complexes; solid tumors
• ISSN: 1543-8384; 1543-8392; 1543-8392
• DOI: 10.1021/mp100122k

In animal models, successful anticancer monotherapy with CpG oligodeoxynucleotide (ODN) has been limited to the intratumoral and peritumoral routes of administration. To overcome this limitation, we developed a delivery system utilizing an endogenous antibody as a carrier for CpG ODNs. When a 1:1 conjugate of 2,4-dinitrophenyl (DNP) to a CpG ODN was administered to tumor-bearing mice that were preimmunized against DNP, intravenous (iv) administration successfully inhibited tumor growth (Palma, E.; Cho, M. J. J. Controlled Release 2007, 120, 95−103). In the present studies, we reproduced the iv results and showed that a DNP derivative of a controlled ODN with scrambled nucleotide sequence failed in the same model. Perhaps more significantly, contralateral subcutaneous (sc) routes of administration also suppressed tumor growth. However, in a separate experiment, when the anti-DNP titer level was low, the antitumor effect was abolished, supporting the importance of the avidity involved in the complexation. With the low titer, a significant fraction of injected dose must have existed as unbound that is subject to rapid clearance. The present study justifies chemically cross-linked immune complexes such that the CpG ODN cannot dissociate in the body after administration.