Design and Fabrication of Multifunctional Sericin Nanoparticles for Tumor Targeting and pH-Responsive Subcellular Delivery of Cancer Chemotherapy Drugs

AbstractIn the present work, we constructed nanoscale graphene oxide (NGO) as a drug nanocarrier to improve the process of tumor-targeted drug releases, promote cellular uptake and accumulation of chemotherapy drugs in tumor tissues, and reduce the toxic effects of chemotherapy drugs on normal cells. Hence, great stability was obtained in the biological solution. Moreover, we designed an effective nanoparticle system for the doxorubicin (DOX) delivery targeting the oral squamous cell carcinoma (OSCC) by mediating the HN-1 (TSPLNIHNGQKL) through hydrogen and π–π bonds. DOX@NGO-PEG-HN-1 showed significantly higher cellular uptakes and cytotoxicity in OSCC cells (CAL-27 and SCC-25), compared to free DOX. Moreover, HN-1 showed considerable tumor-targeting and competition inhibition phenomenon. As we expected, the nanocarrier showed pH-responsive drug release. In total, our study represented a good technique to construct OSCC-targeted delivery of nanoparticles and improve the anticancer medicines’ efficiency.

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Selective Inhibitors of Histone Deacetylase 10 (HDAC-10)

Current Medicinal Chemistry ◽

10.2174/0929867328666210901144658 ◽

2021 ◽

Vol 28 ◽

Author(s):

Eftiola Pojani ◽

Daniela Barlocco

Keyword(s):

Histone Deacetylase ◽

Cancer Chemotherapy ◽

Chemotherapy Resistance ◽

Hdac Inhibitors ◽

Selective Inhibition ◽

Epigenetic Mechanism ◽

Inhibitory Potency ◽

Chemotherapy Drugs ◽

Hydrogen Bond Interactions ◽

Class I Hdacs

: Histone acetylation balance is one epigenetic mechanism controlling gene expression associated with disease progression. It has been observed that histone deacetylase 10 (HDAC-10) isozyme contributes to the chemotherapy resistance; in addition, the poor clinical outcome observed in patients with aggressive solid tumors, such as neuroblastoma, has been associated with its overexpression. Moreover, HDAC-10 selective inhibition suppresses the autophagic response, thus providing an improved risk-benefit profile compared to cytotoxic cancer chemotherapy drugs. On these bases, HDAC-10 is becoming an emerging target for drug design. Due to the rapid progress in the development of next-generation HDAC inhibitors, this review article aims to provide an overview on novel selective or dual HDAC-8/10 inhibitors, as new leads for cancer chemotherapy, able to avoid the severe side-effects of several actual approved “pan” HDAC inhibitors. A literature search was conducted in MedLine, PubMed, Caplus, SciFinder Scholar databases from 2015 to the present. Since the disclosure that the HDAC-6 inhibitor Tubastatin A was able to bind HDAC-10 efficiently, several related analogues were synthesized and tested. Both tricyclic (25-30) and bicyclic (31-42) derivatives were considered. The best pharmacological profile was shown by 36 (HDAC-10 pIC50 = 8.4 and pIC50 towards Class I HDACs from 5.2–6.4). In parallel, based on the evidence that high levels of HDAC-8 are a marker of poor prognosis in neuroblastoma treatment, dual HDAC-8/10 inhibitors were designed. The hydroxamic acid TH34 (HDAC-8 and 10 IC50 = 1.9 µM and 7.7 µM, respectively) and the hybrid derivatives 46d, 46e and 46g were the most promising both in terms of potency and selectivity. Literature surveys indicate several structural requirements for inhibitory potency and selectivity towards HDAC-10, e.g., electrostatic and/or hydrogen bond interactions with E274 and complementarity to the P(E,A) CE motif helix.

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