4 research outputs found
Radiofrequency ablation of drug-resistant cancer cells using molecularly targeted carboxyl-functionalized biodegradable graphene
Rationally Designed Aberrant Kinase-Targeted Endogenous Protein Nanomedicine against Oncogene Mutated/Amplified Refractory Chronic Myeloid Leukemia
Deregulated protein kinases play a very critical role
in tumorigenesis,
metastasis, and drug resistance of cancer. Although molecularly targeted
small molecule kinase inhibitors (SMI) are effective against many
types of cancer, point mutations in the kinase domain impart drug
resistance, a major challenge in the clinic. A classic example is
chronic myeloid leukemia (CML) caused by BCR-ABL fusion protein, wherein
a BCR-ABL kinase inhibitor, imatinib (IM), was highly successful in
the early chronic phase of the disease, but failed in the advanced
stages due to amplification of oncogene or point mutations in the
drug-binding site of kinase domain. Here, by identifying critical
molecular pathways responsible for the drug-resistance in refractory
CML patient samples and a model cell line, we have rationally designed
an endogenous protein nanomedicine targeted to both cell surface receptors
and aberrantly activated secondary kinase in the oncogenic network.
Molecular diagnosis revealed that, in addition to point mutations
and amplification of oncogenic BCR-ABL kinase, relapsed/refractory
patients exhibited significant activation of STAT5 signaling with
correlative overexpression of transferrin receptors (TfR) on the cell
membrane. Accordingly, we have developed a human serum albumin (HSA)
based nanomedicine, loaded with STAT5 inhibitor (sorafenib), and surface
conjugated the same with holo-transferrin (Tf) ligands for TfR specific
delivery. This dual-targeted âtransferrin conjugated albumin
bound sorafenibâ nanomedicine (TfânAlb-Soraf), prepared
using aqueous nanoprecipitation method, displayed uniform spherical
morphology with average size of âŒ150 nm and drug encapsulation
efficiency of âŒ74%. TfR specific uptake and enhanced antileukemic
activity of the nanomedicine was found maximum in the most drug resistant
patient sample having the highest level of STAT5 and TfR expression,
thereby confirming the accuracy of our rational design and potential
of dual-targeting approach. The nanomedicine induced downregulation
of key survival pathways such as pSTAT5 and antiapoptotic protein
MCL-1 was demonstrated using immunoblotting. This study reveals that,
by implementing molecular diagnosis, personalized nanomedicines can
be rationally designed and nanoengineered by imparting therapeutic
functionality to endogenous proteins to overcome clinically important
challenges like molecular drug resistance