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 effecti
ve 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 leu
kemia (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 ad
vanced 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 ha
ve rationally designed an endogenous protein nanomedicine targeted to both cell surface receptors and aberrantly acti
vated secondary
kinase in the oncogenic networ
k. Molecular diagnosis re
vealed that, in addition to point mutations and amplification of oncogenic BCR-ABL
kinase, relapsed/refractory patients exhibited significant acti
vation of STAT5 signaling with correlati
ve o
verexpression of transferrin receptors (TfR) on the cell membrane. Accordingly, we ha
ve de
veloped 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 deli
very. This dual-targeted 鈥渢ransferrin conjugated albumin bound sorafenib鈥?nanomedicine (Tf鈥搉Alb-Soraf), prepared using aqueous nanoprecipitation method, displayed uniform spherical morphology with a
verage size of 150 nm and drug encapsulation efficiency of 74%. TfR specific upta
ke and enhanced antileu
kemic acti
vity of the nanomedicine was found maximum in the most drug resistant patient sample ha
ving the highest le
vel 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 sur
vi
val pathways such as pSTAT5 and antiapoptotic protein MCL-1 was demonstrated using immunoblotting. This study re
veals that, by implementing molecular diagnosis, personalized nanomedicines can be rationally designed and nanoengineered by imparting therapeutic functionality to endogenous proteins to o
vercome clinically important challenges li
ke molecular drug resistance.
Keywords:
kemia&qsSearchArea=searchText">chronic myeloid leukemia; drug resistance; targeted nanomedicine; rational design; albumin; transferrin