Abstract
<p class="MsoBodyText" style="text-indent:0in; text-align:justify"><span style="font-size:12.0pt"><span style="font-family:"Century",serif">Nanotherapeutics is an emerging and powerful tool in cancer treatment and diagnostic with improved targeting ability, drug solubility, and in achieving higher therapeutic index with lower side effects.</span></span><span style="font-size:12.0pt"><span style="font-family:"Century",serif">[1]</span></span> <span style="font-size:12.0pt"><span style="font-family:"Century",serif">However, the delivery of nanotherapeutics remains low due to the contrasting physicochemical requirement of the nanotherapeutics at different delivery stages.</span></span><span style="font-size:12.0pt"><span style="font-family:"Century",serif">[1]</span></span> <span style="font-size:12.0pt"><span style="font-family:"Century",serif">Additionally, accumulation of nanomaterials and their fate in the body has raise much concern over the long-term toxicity. </span></span><span style="font-size:12.0pt"><span style="font-family:"Century",serif">Boron neutron capture therapy (BNCT) is an emerging cancer therapy modality that could deliver an immense gradient of radiation doses within cellular spatiality.</span></span><span style="font-size:12.0pt"><span style="font-family:"Century",serif">[2]</span></span><span style="font-size:12.0pt"><span style="font-family:"Century",serif"> BNCT has resulted in a high response rate (63-80%) for gliomas, recurrent, and metastatic head and neck squamous cell carcinoma (HNSCC) patients with low toxicity. However, BCNT remained the final line of defense for cancer treatment in most countries, except for Japan. The major barrier for BNCT is the lack of preclinical evidence to warrant costly biodistribution and clinical studies. In small clinical trials, the major failure of BNCT is due to local recurrence after BNCT. Non-conclusive results in both preclinical and clinical trials could be due to insufficient and non-homogeneous uptake of boron drug within the tumor, insufficient radiation dose, or clinical target volume (CTV). To solve the foremost challenges in delivering a high concentration of B-10 into the tumor cell is to develop a new, “smart” boron nanotherapeutics. To overcome these challenges, o</span></span><span style="font-size:12.0pt"><span style="font-family:"Century",serif">ur group is developing a pH-sensitive self-assembled boron carbon oxynitride nanoparticles (D ~ 30-160 nm) as a potential boron-based nanodrug for boron neutron capture therapy (BNCT) that is capable of delivering a high B10 content without relying on B-10 enrichment sources. The engineered boron nanodrug is capable of delivering high concentration of B-10 to the tumor site and to cause lethal damage to the only cancer cell while sparing the neighboring health cell via BNCT. On the other hand, immunotherapy has received tremendous research attention due to its clinical success and is regarded as one of cancer treatment pillars in the 21st century. However, immunotherapy is limited to a small subset of the patient population. Patients who responded to immunotherapy also suffers from immunotoxicity and autoimmunity, which compromise therapeutic benefits. Combination of immune checkpoint blockade treatment with other immunotherapy agents or conventional cancer therapy (i.e., chemotherapy, radiation therapy) changes the cancer treatment paradigm.</span></span><span style="font-size:12.0pt"><span style="font-family:"Century",serif">[3]</span></span><span style="font-size:12.0pt"><span style="font-family:"Century",serif"> Though, combinational therapies using multiple drugs that have different pharmacokinetics, biodistribution, and mechanism of action are challenging to harness their synergistic effects, in addition to the increase in toxicity.</span></span></p><p class="MsoBodyText" style="text-indent:0in; text-align:justify"><span style="font-size:0.875rem;"><span style="font-family:"Times New Roman",serif">Herein, we present the preparation of a stimuli-responsive polymer-coated BCNO nanoparticle (D~ 6 nm) that self-assembled into 160 nm nanostructures bearing a negative surface charge for optimal tumor accumulation via the EPR effect. The mouse anti-PD-L1 immune check point inhibitor will be conjugated onto the polymer-coated BNCO nanoassemblies. The engineered combined immuno-neutron capture therapy nanocarrier will disintegrate into individual positively charged BCNO nanoparticles. The positively charged BCNO nanoparticles not only possessed enhanced cell internalization and diffusional properties throughout the solid tumor for effective BNCT, but could also be eliminated through renal clearance after treatment. Simultaneous, the same acid-labile linker used in conjugating the mouse anti-PD-L1 cleaves enabling the blockage of the PD-1/PD-L1 signaling pathway, thus activating immune cell death (ICD) at the tumor site through immune check point blockade therapy without causing systemic toxicity. (Figure 1) Previously, we have demonstrated the modulation of BCNO nanoparticles cytotoxicity and cell uptake by proper engineering of the BCNO surface with appropriate polymer ligands.[4] We have also demonstrated our first proof-of-concept principle on the tumoricidal effect of the brain tumor cell treated with the self-assembled BCNO nanodrug via BNCT surpassing the treatment efficient using the state-of-the-art boron-10 drug. (Figure 2) In this paper, we will present the self-assembly mechanism of the BCNO nanoparticles within a double hydrophilic block copolymer to achieve a highly tunable self-assembled boron nanostructures. We will also present our preliminary result in the conjugation of the anti-mouse PD-L1 onto the boron nanoassemblies, their stability at physiological pH and the released rate under slightly acidic condition. We anticipate that the development of a simple and modular methodology in self-assembling nanoparticles as nanotheranostic could advanced BNCT and revolutionized cancer treatment. </span></span></p><p class="MsoBodyText" style="text-indent:0in; text-align:justify"> </p>