A new insight into the reversal of multidrug resistance in cancer by nanodrugs.

Although nanodrugs have been shown to evade P-glycoprotein (P-gp) recognition and reverse multi-drug resistance (MDR) in cancer, a specific mechanism of how nanodrugs reverse MDR is still unclear. Herein, we investigate the underlying MDR reversal mechanism by studying the in vitro behaviors of model nanodrugs, including internalization, intracellular drug release and intracellular drug enrichment. Comprehensive experimental results showed that the internalization process of nanodrugs can change the distribution of P-gp in MDR cells and significantly reduce the P-gp level in the cell membrane, which might be the key step for MDR reversal. This work offers novel mechanistic insights into MDR reversal by nanodrugs, and this process involves reducing the P-gp distribution ratio in the cell membrane through unique cell internalization behavior rather than merely evading P-gp recognition. Moreover, we further demonstrated that the MDR reversal capacity of nanodrugs follows a size-dependent pattern.

Self-Assembled Polyprodrug Amphiphile for Subcutaneous Xenograft Tumor Inhibition with Prolonged Acting Time In Vivo.

Polymeric drug delivery system termed as "polyprodrug amphiphile" poly(2-methylacryloyloxyethyl phosphorylcholine)-b-poly(10-hydroxy-camptothecin methacrylate (pMPC-b-pHCPT) is developed for the prolonged-acting cancer therapy. It is obtained by two-step reversible addition-fragmentation chain transfer polymerization of zwitterionic monomer MPC and an esterase-responsive polymerizable prodrug methacrylic anhydride-CPT, respectively. This diblock polymer is composed of both antifouling (pMPC) and bioactive (pHCPT) segments and the drug is designed as a building block to construct the polymer skeleton directly. Due to its distinct amphiphilicity, the polymer can self-assemble into micelles with different dynamic sizes by facilely tuning the ratio of MPC/HCPT under physiological conditions. The outer pMPC shell is superhydrophilic to form dense hydrate layer preventing the nanosystem from unwanted nonspecific protein adsorption, which is the main lead cause of the rapid clearance of nanoparticles in vivo, thus facilitating the accumulation of drugs in tumor sites via enhanced permeability and retention effect. The configuration of the polyprodrug amphiphile is confirmed by several measurements. The resistance to albumin adsorption, prolonged plasma retention time, accumulation in tumor sites, and anticancer activity of the micelles is also investigated in vitro and in vivo. This novel amphiphile can be expected as a promising agent for the passive targeted prolonged-acting cancer therapy.

Zwitterionic gold nanorods: low toxicity and high photothermal efficacy for cancer therapy.

Novel "zwitterionic" gold nanorods (Au NRs) were constructed through a facile ligand exchange process between cetyltrimethylammonium bromide (CTAB)-Au NRs and the zwitterionic block polymer {poly(2-methacryloyloxyethyl phosohorylcholine)-b-poly(lipoic methacrylate) (pMPC-b-pLA)}. In vitro, they exhibited low dark cytotoxicity and a high therapeutic efficacy to cancer cells. Their blood circulation half-life in vivo (t1/2, ∼10 h) was 20-fold longer than that of CTAB-Au NRs (t1/2, <30 min). After intravenous administration, they accumulated in tumour sites via an enhanced permeability and retention (EPR) effect and enabled destruction of human xenograft tumours in mice after exposure of the tumour location to NIR laser irradiation at 808 nm. These studies showed that the "zwitterionic" Au NRs had low toxicity and high photothermal efficacy both in vitro and in vivo due to the suprahydrophilic, biocompatible zwitterionic polymer coating layer. They may have the potential to be a promising NIR PTT agent in the biomedical field.

Thin-layer polymer wrapped enzymes encapsulated in hierarchically mesoporous silica with high activity and enhanced stability.

A novel soft-hard cooperative approach was developed to synthesize bioactive mesoporous composite by pre-wrapping Penicillin G amidase with poly(acrylaimde) nanogel skin and subsequently incorporating such Penicillin G amidase nanocapsules into hierarchically mesoporous silica. The as-received bioactive mesoporous composite exhibited comparable activity and extraordinarily high stability in comparison with native Penicillin G amidase and could be used repetitively in the water-medium hydrolysis of penicillin G potassium salt. Furthermore, this strategy could be extended to the synthesis of multifunctional bioactive mesoporous composite by simultaneously introducing glucose oxidase nanocapsules and horseradish peroxidase nanocapsules into hierarchically mesoporous silica, which demonstrated a synergic effect in one-pot tandem oxidation reaction. Improvements in the catalytic performances were attributed to the combinational unique structure from soft polymer skin and hard inorganic mesoporous silica shell, which cooperatively helped enzyme molecules to retain their appropriate geometry and simultaneously decreased the enzyme-support negative interaction and mass transfer limitation under heterogeneous conditions.