Abstract
BackgroundSystemic administration of chemotherapeutic agents, in addition to its anti-tumor benefits, results in indiscriminate drug distribution and severe toxicity. This shortcoming may be overcome by targeted drug-carrying platforms that ferry the drug to the tumor site while limiting exposure to non-target tissues and organs.ResultsWe present a new form of targeted anti-cancer therapy in the form of targeted drug-carrying phage nanoparticles. Our approach is based on genetically-modified and chemically manipulated filamentous bacteriophages. The genetic manipulation endows the phages with the ability to display a host-specificity-conferring ligand. The phages are loaded with a large payload of a cytotoxic drug by chemical conjugation. In the presented examples we used anti ErbB2 and anti ERGR antibodies as targeting moieties, the drug hygromycin conjugated to the phages by a covalent amide bond, or the drug doxorubicin conjugated to genetically-engineered cathepsin-B sites on the phage coat. We show that targeting of phage nanomedicines via specific antibodies to receptors on cancer cell membranes results in endocytosis, intracellular degradation, and drug release, resulting in growth inhibition of the target cells in vitro with a potentiation factor of >1000 over the corresponding free drugs.ConclusionThe results of the proof-of concept study presented here reveal important features regarding the potential of filamentous phages to serve as drug-delivery platform, on the affect of drug solubility or hydrophobicity on the target specificity of the platform and on the effect of drug release mechanism on the potency of the platform. These results define targeted drug-carrying filamentous phage nanoparticles as a unique type of antibody-drug conjugates.
Highlights
Systemic administration of chemotherapeutic agents, in addition to its anti-tumor benefits, results in indiscriminate drug distribution and severe toxicity
Binding analysis with monoclonal antibodies complexed phage nanoparticles using whole cell ELISA The comparative binding analysis was done by whole-cell ELISA as described in Materials and Methods
This study presents targeted, drug carrying filamentous bacteriophages as a drug delivery platform for targeting cancer cells
Summary
Systemic administration of chemotherapeutic agents, in addition to its anti-tumor benefits, results in indiscriminate drug distribution and severe toxicity. This shortcoming may be overcome by targeted drug-carrying platforms that ferry the drug to the tumor site while limiting exposure to non-target tissues and organs. Since the introduction of monoclonal antibodies (mAbs), and the initial clinical trials of antibody therapy in cancer patients, there has been progress in antibody based therapeutics, in oncology. In general drug immunoconjugates are composed of targeting entities (mainly mAbs) chemically conjugated to a cytotoxic drug. The most clinically-advanced forms of armed antibodies are antibody-isotope and antibody-drug conjugates [1,2,3]. Key issues in designing and testing immunoconjugates include: 1. the nature of the target molecule, its abundance at the target, whether it is internalizing and at what rate, and its specificity to the target,
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