Category: Micro- and Nanotechnologies
Metastasis is a major cause of mortality in breast cancer patients in part due to lack of clinically established targeted therapies.
Among the different types of breast cancer, triple negative breast cancer (TNBC) (ER-, PR-, and HER2-) has been associated with
poor prognosis and survival rate due to early metastasis to other organs and a lack of clinically established targeted therapies. Hence,
development of novel targeted therapies that prevent metastasis and improve efficacy of currently available chemotherapeutic agents
for TNBC is a need of hour.
Receptor for advanced glycation end-products (RAGE) is a multi-ligand cell-surface receptor belongs to immunoglobulin super
family. It was reported that, interaction of RAGE with its ligands like, advanced glycation end products (AGE), S100/Calgranulin,
HMGB1 and the S100 family of proteins (S100A4, S100A6, S100A7, S100A9) stimulate P38 and P44/42, MAP kinase ,Rasextracellular
signal-regulatedkinase and NF-κB to promote tumour progression and metastasis (by promoting epithelial-tomesenchymal
transition) in TNBC. We, therefore, hypothesize that RAGE-targeted delivery of cytotoxic drugs might have potential
to achieve radical cure by selectively targeting TNBC and preventing metastasis. As a proof of the concept in this study, we propose
anti-RAGE antibody bioconjugated lipid nanovehicles encapsulated with proteasome inhibitor, bortezomib (BTZ), that can
discriminate TNBC cells and healthy cells based on RAGE expression.
Anti-RAGE antibody selectively targets of TNBC cells, due to their overexpression of RAGE and silence the downstream signaling
required for metastasis. BTZ affects the protein homeostasis of cancer cells, to enhance tumor regression. The developed anti-RAGE
antibody conjugated lipid nanocarriers (RAGE-BTZ) have appreciable size of 132±1.72 nm and encapsulation efficiency of 85.60 %.
RAGE-BTZ nanocarriers exhibited 4-fold decrease of IC50 when compared to BTZ against MDA-MB-231 cell lines. These
nanocarriers exhibited successful internalization in RAGE overexpressed MDA-MB-231 cell lines determined fluorescence staining
method. By the Western blot analysis, caspase-9 and -3 were significantly up-regulated while the Bcl-2 down regulated suggesting
activation of apoptosis. Down-regulation of MMP-9, MMP2 and EMT markers implies the inhibition of angiogenesis and metastasis.
Overall, the RAGE targeting in combination with cytotoxic agents like, BTZ represent an attractive approach for treating metastatic
Satya Sesha Sai Kira Pindiprolu– Ph.D. Student, JSS University, Tamil Nadu, Tamil Nadu, India
Tamil Nadu, Tamil Nadu, India
Currently I am Ph.D. Student at Department of Pharmacology, JSS College of Pharmacy, Ooty, JSS University, Mysuru, India. I
have obtained my B.Pharm degree from Andhra University, Visakhapatnam and M.Pharm. degree from JSS University, Mysuru,
India. My research interests include development of site specific drug delivery systems for treatment of cancer. I have published
my research findings in reputed journals like Drug delivery, Artificial cells, Nanomedicine and biotechnology, Medical
Hypotheses and European Journal of Cancer. I have received Travel grants from Indian Council of Medical Research and Centre
for International co-operation in Science (CICS), Chennai, to attend International Conference on Cancer Care and Cure,2016,
held at Dubai, UAE. I have also qualified national level Graduate Pharmacy Aptitude Test with an all India rank of 1565.