Multiple-Responsive Nanoparticles For The Delivery Of Boronic Acid-bearing Therapeutics Agents

Bortezomib（BTZ）is the first-line boronic acid-bearing proteasome inhibitor for cancer treatment,but its clinical effect is limited by hematotoxicity and other adverse effects.Nanocarriers that can responsively release its payloads in the tumor micro-environment are designed to alleviate the adverse effects and further improve the anticancer effect of BTZ.Previous studies mainly constructed nanocarriers through the interaction between catechol and boronic acid.However,the catechol group is prone to be oxidized.In this research,we designed a multi-responsive release nanocarrier based on amine-modified polyhedral oligomeric silsesquioxane-polyethylene glycol（POSS-PEG）through the donor-acceptor interaction between boronic acid and amino groups.The site-selective functionalization of POSS has been realized efficiently by the“click”reaction.In the amine-modified POSS-PEG,one site of POSS is linked with PEG to reduce the non-specific absorption of proteins to nanoparticles（NPs）in blood;and the other seven sites are modified with amino groups to interact with boronic acid-bearing drugs,obtaining（NH₂）₇-POSS-PEG（NPP）.Firstly,the model molecule（TPE-BOH）with aggregation-induced emission（AIE）effect was encapsulated into NPP to prepare nanoparticles,TPE@NPs.After systematical optimization of the formulation,TPE@NPs with the average diameter of 166 nm and the drug loading of7%was obtained.It is important to introduce the donor-acceptor interaction and the imine bond simultaneously to prepare stable NPs.The TPE@NPs responsively release its payloads under the trigger of weak acidic conditions or fluoride（F^-）solution.Also,the cell imaging experiment has proved that TPE@NPs at a safe dose（200μg/ml）can effectively enter 4T1cells.After that,BTZ was encapsulated into NPP in a similar formulation,obtaining BTZ@NPs with the average diameter of 142 nm and the drug loading of 5.6%.Studies in vitro have proved that BTZ@NPs can reduce the toxic adverse effect.At the same BTZ concentration（5μg/ml）,BTZ@NPs have effectively suppressed 4T1（the viability is 29.8±0.3%）while have shown little effect on HUVEC（the viability is 84±10%）.Furthermore,when the concentration of BTZ was 0.01μg/ml,the viability of 4T1（47±5%）under the weak acidic condition（p H 6.5）was lower than that（63±8%）under the neutral condition,indicating that the p H-responsive release of BTZ@NPs enhanced the suppression to 4T1.This work prepared a nanocarrier based on POSS through efficient synthesis,that effectively interacts with boronic acid-bearing drugs,providing a drug delivery platform for the multiple-responsive release of BTZ.