A single dose of doxorubicin-functionalized bow-tie dendrimer cures mice bearing C-26 colon carcinomas - PubMed (original) (raw)

A single dose of doxorubicin-functionalized bow-tie dendrimer cures mice bearing C-26 colon carcinomas

Cameron C Lee et al. Proc Natl Acad Sci U S A. 2006.

Abstract

The antitumor effect of doxorubicin (DOX) conjugated to a biodegradable dendrimer was evaluated in mice bearing C-26 colon carcinomas. An asymmetric biodegradable polyester dendrimer containing 8-10 wt % DOX was prepared. The design of the dendrimer carrier optimized blood circulation time through size and molecular architecture, drug loading through multiple attachment sites, solubility through PEGylation, and drug release through the use of pH-sensitive hydrazone linkages. In culture, dendrimer-DOX was >10 times less toxic than free DOX toward C-26 colon carcinoma cells after exposure for 72 h. Upon i.v. administration to BALB/c mice with s.c. C-26 tumors, dendrimer-DOX was eliminated from the serum with a half-life of 16 +/- 1 h, and its tumor uptake was ninefold higher than i.v. administered free DOX at 48 h. In efficacy studies performed with BALB/c mice bearing s.c. C-26 tumors, a single i.v. injection of dendrimer-DOX at 20 mg/kg DOX equivalents 8 days after tumor implantation caused complete tumor regression and 100% survival of the mice over the 60-day experiment. No cures were achieved in tumor-implanted mice treated with free DOX at its maximum tolerated dose (6 mg/kg), drug-free dendrimer, or dendrimer-DOX in which the DOX was attached by means of a stable carbamate bond. The antitumor effect of dendrimer-DOX was similar to that of an equimolar dose of liposomal DOX (Doxil). The remarkable antitumor activity of dendrimer-DOX results from the ability of the dendrimer to favorably modulate the pharmacokinetics of attached DOX.

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1.

Fig. 1.

Cartoon representation of two bow-tie dendrimers with the same mass of PEO attached (40,000 Da). The more compact [G-3]-(PEO5k)8-[G-3]-(OH)8 dendrimer on the left is composed of eight 5,000-Da PEO chains attached to one side of the dendrimer; the less branched [G-1]-(PEO20k)2-[G-3]-(OH)8 dendrimer on the right is composed of two 20,000-Da PEO chains attached to one side of the dendrimer. The other half of each dendrimer is used for drug attachment and is presumably wrapped and shielded by the PEO chains to some extent.

Fig. 2.

Fig. 2.

Functionalization of the [G-3]-(PEO5k)8-[G-4]-(OH)16 bow-tie dendrimers for therapeutic studies. DOX is linked to the bow tie by means of a carbamate (top) or acyl hydrazone (middle) linkage. In the bottom route, hydrazide groups of the bow tie are blocked upon reaction with acetone. The top and bottom bow ties represent control treatments.

Fig. 3.

Fig. 3.

Survival versus time for BALB/c mice bearing s.c. C-26 tumors. In a, treatment consisted of a single i.v. dose of hydrazone-linked bow-tie DOX given 8 days after tumor implantation. In b, treatment consisted of a single i.v. injection of either free DOX or Doxil given 8 days after tumor implantation. Doses (in DOX equivalents) are specified in the key. (n = 10 for each group.)

References

    1. Duncan R. Nat Rev Drug Discov. 2003;2:347–360. - PubMed
    1. Drobník J, Rypácek F. Adv Polym Sci. 1984;57:1–50.
    1. Allen TM, Cullis PR. Science. 2004;303:1818–1822. - PubMed
    1. Hobbs SK, Monsky WL, Yuan F, Roberts WG, Griffith L, Torchilin VP, Jain RK. Proc Natl Acad Sci USA. 1998;95:4607–4612. - PMC - PubMed
    1. Hashizume H, Baluk P, Morikawa S, McLean JW, Thurston G, Roberge S, Jain RK, McDonald DM. Am J Pathol. 2000;156:1363–1380. - PMC - PubMed

Publication types

MeSH terms

Substances

LinkOut - more resources