Blockade of CD73 using siRNA loaded chitosan lactate nanoparticles functionalized with TAT-hyaluronate enhances doxorubicin mediated cytotoxicity in cancer cells both in vitro and in vivo

Chemotherapy drugs are still one of the first treatment options used in many cancers; however, problems such as
cytotoxic side effects on normal cells after systemic administration and resistance to treatment have reduced the
use of chemotherapeutics day by day. Targeted delivery of these drugs to the tumor site and sensitization of
cancer cells to death induced by chemotherapy drugs are ways that can overcome the limitations of the use of
these drugs. In this study, we designed and generated a novel nanocarrier composed of chitosan lactate nanoparticles
(NPs) functionalized by HIV-1 derived TAT peptide (Transactivating transcriptional activator) and
hyaluronate (HA) to deliver CD73 siRNA and doxorubicin to 4T1 and CT26 cancer cells, both in vivo and in vitro,
as a novel combinatorial treatment strategy. The CD73 molecule plays a key role in many cancer cell behaviors
such as proliferation, angiogenesis, metastasis, imunosuppression, and resistance to chemotherapy. Therefore,
we decided to reduce the side effects of DOX by simultaneously transmitting CD73 siRNA and DOX by CL-TATHA
NPs, increase the susceptibility of cancer cells to DOX-induced cell death, and stimulate anti-tumor immune
responses, for the first time. These results indicated that simultaneous transfer of CD73 siRNA and DOX to cancer
cells (4 T1 and CT26) increased cell death and inhibited the prolifration and spread of cancer cells. Also, the
preferential aggregation of NPs in the tumor microenvironment reduced tumor growh, promoted the survival of
tumor-bearing mice, and induced anti-tumor immune responses. These findings indicate that CL-TAT-HA NPs are
a good candidate for targeted siRNA/drug delivery to cancer cells and the simultaneous transfer of CD73 siRNA
and DOX to cancer cells using this nanocarrier can be used to treat cancer.