Hepatic carcinoma (HCC) is a lethal disease associated with high morbidity and poor prognosis. Recently years, gene therapies have offered novel modalities to improve the prognosis of HCC patients. MicroRNA-99a (miR-99a) is frequently down-regulated in HCC, where it acts as a tumor suppressor. Therefore, we constructed monomethoxy (polyethylene glycol)-poly(D,L-lactide-co-glycolide)-poly(L-lysine)-lactobionic acid- anti-vascular endothelial growth factor antibody (mPEG-PLGA-PLL-LA/VEGFab or PEAL-LA/VEGFab) nanoparticles (NPs) with highly specific targeting properties as carriers to restore the expression of miR-99a both in vitro and in vivo, to inhibit HCC progression. In vitro, PEAL-LA/VEGFab NPs showed more efficient delivery of miR-99a to HepG2 cells than the conventional transfection reagent Lipofectamine^TM2000 (Lip2000). The higher delivery efficiency associated with PEAL-LA/VEGFab NPs consequently resulted in down-regulation of target genes and suppression of the proliferation, migration and invasion of HepG2 cells. In vivo, miR-99a-PEAL-LA/VEGFab NPs inhibited tumor xenograft growth in HCC-bearing mice without causing obvious systemic toxicity. Our results demonstrate that PEAL-LA/VEGFab NPs selectively and effectively deliver miR-99a to HCC cells based on the double-targeting character of these nanoparticles, thereby offering potential for translation into effective clinical therapies for HCC.

Pancreatic cancer characterized with intense hydraulic tissue in tumor extracellular matrix (ECM) resists most of chemotherapeutic drugs. Increased levels of hyaluronic acid (HA) represent the primary component of the hydraulic tissue, rendering tumors protective from drug targeting. Quercetin (Que), a natural flavonoid, has the ability to inhibit tumor cell growth in a number of cancers; however, its poor water solubility and low bioavailability largely limit its application in cancer therapy. Hence, we developed an efficient drug delivery system by encapsulation of Que. into liposomes and conjugation with hyaluronidase (HAase) at liposome surface, termed as HQL. In the presence of HAase, HQL were predominantly accumulated at tumor with enhanced permeability and retention effect. Treatment of xenografted tumor mice with HQL gave rise to suppressed tumor growth, while no toxic effects were observed in mice. HQL demonstrated the strong ability to inhibit cell proliferation, promote cell apoptosis, and induce arrest at G2/M cell cycle in pancreatic cancer lines, three-dimensional cultured cell spheroids and pancreatic ductal adenocarcinoma (PDAC)-derived organoids. Mechanistically, HQL downregulated expression of cell cycle-associated protein (CCNB1, CDK1 and PLK1) and cell apoptosis-associated factors PI3K/AKT and Bcl-2. In summary, HQL degraded HA in the tumor microenvironment to enhance nano-particle penetration and inhibited tumor cell growth, eliciting efficacy of anti-tumor therapy. Thereof, HQL may provide a novel efficient drug delivery approach for the adjuvant treatment of pancreatic cancer.

Dendrimer, such as dendrigraft poly-L-lysine (DGL) polymers, with high surface charge density, well-defined structure, and narrow poly-dispersity is often employed as a gene vector, but its transfection efficiency is still partially inhibited due to poor endosomal escape ability. Herein, we used a surface modification strategy to enhance the endosomal escape ability of DGL polymers, and thus improved its gene transfection efficiency. A library of phenylboronic acid (PBA) modified DGL polymers (PBA-DGLs) was designed to screen efficient small interfering RNA (siRNA) vectors. The lead candidate screened from the library shown a capability of inducing nearly 90% gene silencing in MDA-MB-231 cells. The study of the transfection mechanism revealed that PBA modification not only improves siRNA cellular uptake, but, more importantly, endows DGL polymers the ability of endosomal escape. One of the top candidates from polyplexes was further shielded with hyaluronic acid to construct targeted nanoparticles, and the yielding nanoparticles significantly suppressed the tumor growth in a breast cancer model by effective siRNA delivery. This research provides a general and effective strategy to enhance the endosomal escape and transfection efficiency of dendrimer.

Fe 3 O 4 nanoparticles and cryoablation enhance ice crystal formation to improve the efficiency of killing breast cancer cells Fe3O4 nanoparticles and cryoablation enhance ice crystal formation to improve the efficiency of killing breast cancer cells

The ultrasmall nanoparticles easily lead to a more seriously response than larger nanoparticles because of their physicochemical features. It is essential to understand their cytotoxicity effects for their further application. Here, we used ultrasmall 9 nm Fe₃O₄ NPs to explore its cytotoxicity mechanism on breast cancer cells. We demonstrated 9 nm Fe₃O₄ NPswas effectively internalized into cells and located in nucleus, subsequently, it inhibited DNA synthesis through inducing S-phase arrest.Moreover, 9 nm Fe₃O₄ NPs induced ROS production and oxidative damage by disturbing the expression of antioxidant-related genes (HMOX-1, GCLC and GCLM), which resulted in the enhancement of cells apoptosis and inhibition of cell proliferation, suggesting its potential to be used as therapeutic drug.