PTX prodrug (University of Oklahoma Health Sciences Center)

Efficient drug delivery and deeper penetration into tumors have become a primary focus of anti-tumor nanomedicine. In this study, pyridylboronic acid (BPA), as a targeting ligand for sialic acid, which is highly expressed on the surface of tumor cells, was conjugated with DSPE-PEG2k-NH₂ to synthesize DSPE-PEG2k-BPA and used to encapsulate PTX. The resultant PTX@DSPE-PEG2k-BPA nanoparticles (DPB NPs) showed a mean particle size of 189.0 ± 3.5 nm, with a high drug loading content of 48.75 % and a rod-like morphology. In contrast to PTX@DSPE-mPEG2k nanoparticles (DP NPs), DPB NPs displayed enhanced cellular uptake and targetability to 4T1 tumor cells. Interestingly, BPA modification could also enhance transcytosis through the endoplasmic reticulum-Golgi pathway, thus improving penetration and accumulation of nanoparticles in tumors. An in vivo study on 4T1 tumor-bearing mice demonstrated that DPB NPs achieved a faster and more accumulation in tumors than DP NPs after intravenous administration, led to significantly improved therapeutic efficacy with a higher tumor inhibition rate (74.27 % vs 50.58 %, p < 0.01). In conclusion, the modification of BPA presents a strategy for the development of drug delivery systems that exhibit dual functionalities: active targeting and transcytosis.

Breast cancer is a fatal malignant tumor in women worldwide. The development of paclitaxel resistance remains a challenge. Autophagy is considered to have a significant part in the chemotherapeutic stress mechanism. This study aimed to investigate the function of long non-coding RNA (lncRNA) in breast cancer cell chemoresistance and autophagy. The paclitaxel (PTX)-resistant breast cancer cells were established. The function of X-inactive specific transcript (XIST) was demonstrated using in vitro and in vivo experiments. Transmission electron microscope (TEM) was used to observe autophagy vesicles. Protein and mRNA levels were determined using western blotting and quantitative real time polymerase chain reaction (qRT-PCR). We discovered that autophagic activity was correlated with chemoresistance in PTX-resistant breast cancer cells. In vitro and in vivo studies showed that XIST inhibition reduced cell resistance to paclitaxel, caused autophagy to be suppressed by regulating hsa-let-7d-5p and ATG16L1 expression. Mechanically, threonine protein kinase B (PKB; also known as AKT) - mammalian target of rapamycin (mTOR) pathway was activated when knockdown of XIST, while was reversed by inhibition of hsa-let-7d-5p. Our results verified that XIST played a significant role in developing chemoresistance via mediating autophagy in PTX-resistant breast cancer cells. It may be a potential target for breast cancer treatment strategies.