Specific delivery of corroles to cells via noncovalent conjugates with viral proteins.
OBJECTIVE
Corroles are amphiphilic macrocycles that can bind and transport metal ions, and thus may be toxic to cells. We predicted that anionic corroles would poorly enter cells due to the negatively charged cell membrane, but could be ideal tumor-targeted drugs if appropriate carriers enabled delivery into tumor cells. In this work, we test the hypothesis that recombinant cell penetrating proteins of the adenovirus (Ad) capsid form noncovalent conjugates with corroles to facilitate target-specific delivery and cell death.


METHODS
Corroles mixed with recombinant proteins were tested for conjugate assembly, cell penetration, stability, targeted binding, and cell killing in vitro.


RESULTS
Sulfonated corroles entered cells only with carrier proteins, and formed stable complexes with recombinant Ad capsid proteins. ErbB receptor-targeted conjugates were cytotoxic to ErbB2-positive but not ErbB2-negative breast cancer cells, whereas molar equivalents of free corrole had no effect on these cells.


CONCLUSIONS
Sulfonated corroles are cytotoxic to ErbB2-positive breast cancer cells when delivered by a targeted cell penetrating protein. The relatively low dose required to accomplish this compared to untargeted compounds suggests that corroles may lend themselves to targeted therapy. Importantly, the amphiphilicity of corroles enables a unique approach to bioconjugate formation whereby the carrier and drug form a stable complex by noncovalent assembly.
Agadjanian
Hasmik
H
The Gene Therapeutics Research Institute, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Davis 5092, Los Angeles, California 90048, USA.
Weaver
Jeremy J
JJ
Mahammed
Atif
A
Rentsendorj
Altan
A
Bass
Sam
S
Kim
Jihee
J
Dmochowski
Ivan J
IJ
Margalit
Ruth
R
Gray
Harry B
HB
Gross
Zeev
Z
Medina-Kauwe
Lali K
LK
D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D016503:Drug Delivery Systems; D005456:Fluorescent Dyes; D006367:HeLa Cells; D006801:Humans; D011166:Porphyrins / Q000008:administration & dosage* / Q000493:pharmacokinetics; D011956:Receptors, Cell Surface / Q000187:drug effects / Q000378:metabolism; D014764:Viral Proteins / Q000737:chemistry / Q000494:pharmacology*
D005456:Fluorescent Dyes; D011166:Porphyrins; D011956:Receptors, Cell Surface; D014764:Viral Proteins; C431863:corrole