The Sustainability of Energy Conversion Inhibition for Tumor Ferroptosis Therapy and Chemotherapy.

The hyperactive energy metabolism mostly contributes the tumor cells growth and proliferation. Herein, the intelligent nanoparticles (P-B-D NPs) obtained by loading BAY-876 and doxorubicin (Dox)-Duplex into nanoparticles composed of disulfide bond (SS) containing polymer are reported, which provide an efficient resistance of tumor cells energy metabolism and tumor growth to conquer malignant tumor. In response to the reducing microenvironment of tumor tissue, the SS bond can be disintegrated by intracellular glutathione to block the synthesis of lipid repair enzyme-glutathione peroxidase 4 for ferroptosis therapy. More importantly, the released BAY-876 can inhibit the functionality of glucose transporter 1, restricting the glucose uptake of tumor cells to a low energy metabolism status. Meanwhile, Dox-Duplex can interact with ATP to reduce intracellular ATP content and release Dox to kill tumor cells. Collectively, this work offers a new idea for restricting tumor cells energy metabolism to inhibit their proliferation.

Strategies of Alleviating Tumor Hypoxia and Enhancing Tumor Therapeutic Effect by Macromolecular Nanomaterials.

Hypoxia as one of the most prominent features in tumors, has presented negative effects on tumor therapies including photodynamic therapy, radiotherapy, and chemotherapies, leading to the tumor regeneration and metastasis. Recently, nanomedicines have been proposed to handle the hypoxia dilemma. Some nanomedicines alleviated hypoxia to enhance the therapeutic effect, others used hypoxia-sensitive substances to treat tumor. Among them, macromolecular nanomaterials-based nanomedicine has attracted increased research interest. However, the complicated tumor microenvironment disturbs the practical application of macromolecular nanomaterials to deal with hypoxia. This review highlights the influence of hypoxia on tumor therapy and some new strategies of using macromolecular nanomaterials to overcome hypoxia for effective tumor therapy.

Doxorubicin Loaded Chitosan-W18 O49 Hybrid Nanoparticles for Combined Photothermal-Chemotherapy.

Combined treatment is more effective than single treatment against most forms of cancer. In this work, doxorubicin loaded chitosan-W18 O49 nanoparticles combined with the photothermal therapy and chemotherapy are fabricated through the electrostatic interaction between positively charged chitosan and negatively charged W18 O49 nanoparticles. The in vitro and in vivo behaviors of these nanoparticles are examined by dynamic light scattering, transmission electron microscopy, cytotoxicity, near-infrared fluorescence imaging, and tumor growth inhibition experiment. These nanoparticles have a mean size around 110 nm and show a pH sensitive drug release behavior. After irradiation by the 980 nm laser, these nanoparticles show more pronounced cytotoxicity against HeLa cells than that of free doxorubicin or photothermal therapy alone. The in vivo experiments confirm that their antitumor ability is significantly improved, resulting in superior efficiency in impeding tumor growth and extension of the lifetime of mice.

The effects of poly(zwitterions)s versus poly(ethylene glycol) surface coatings on the biodistribution of protein nanoparticles.

Zwitterionic poly(carboxybetaine) (PCB), poly(2-methacryloyloxyethyl phosphorylcholine) (PMPC) and non-ionic poly(ethylene glycol) (PEG), which have similar degrees of polymerization, were grafted to branched polyethyleneimine (PEI) to generate PCB-grafted PEI (PEI-PCB), PMPC-grafted PEI (PEI-PMPC) and PEG-grafted PEI (PEI-PEG) copolymers, respectively. These grafted PEI copolymers with almost the same grafting number were coated on the surface of 110 nm bovine serum albumin-poly(N-3-acrylamidophenylboronic acid) (BSA-PAPBA) nanoparticles to make a comparison of the surface decoration effect on the biodistribution of nanoparticles. Compared to the nanoparticles without surface decoration, surface decoration with the copolymers significantly prolonged the circulation time of BSA-PAPBA nanoparticles, leading to remarkable enhancement of tumor uptake of the nanoparticles. The drug accumulation at the tumor site reached more than 10% injected dose per gram of tumor. Among them, the PEI-PMPC-decorated nanoparticles exhibited the best performance in tumor accumulation and anticancer ability. Thus, these surface-decorated nanoparticles may serve as a strong candidate for high tumor accumulation of drug delivery systems.

Paclitaxel-Loaded ß-Cyclodextrin-Modified Poly(Acrylic Acid) Nanoparticles through Multivalent Inclusion for Anticancer Therapy.

A nanoassembled drug delivery system for anticancer treatment, formed by the host-guest interactions between paclitaxel (PTX) and ß-cyclodextrin (ß-CD) modified poly(acrylic acid) (PCDAA), is successfully prepared. After such design, the aqueous solubility of PTX is greatly increased from 0.34 to 36.02 µg mL(-1), and the obtained PCDAA-PTX nanoparticles (PCDAA-PTX NPs) exhibit a sustained PTX release behavior in vitro. In vitro cytotoxicity finds that PCDAA-PTX NPs can accumulate significantly in tumor cells and remain the pharmacological activity of PTX. The in vivo real-time biodistribution of PCDAA-PTX NPs is investigated using near-infrared fluorescence imaging, indicating that the PCDAA-PTX NPs can effectively target to the tumor site by the enhanced permeability and retention effect in H22 tumor-bearing mice. Through in vivo antitumor examination, PCDAA-PTX NPs exhibit superior efficacy in impeding the tumor growth compared to the commercially available Taxol®.

Anti-Fas Antibody Conjugated Nanoparticles Enhancing the Antitumor Effect of Camptothecin by Activating the Fas-FasL Apoptotic Pathway.

Emerging evidence suggest that the introduction of Fas ligand (FasL) can enhance the Fas-dependent apoptosis and induce durable immune responses against tumor. However, selective triggering of apoptosis in tumor cells while sparing normal cells remains a great challenge for the application of FasL-based therapeutic strategies. Herein, smart nanoparticles (NPs) with a sandwich structure were fabricated. These NPs consist of a matrix metalloproteinase (MMP) cleavable PEG outer layer, an anti-Fas antibody middle layer, and a camptothecin (CPT)-loaded inner core. They could accumulate at a tumor site by the enhanced permeability and retention (EPR) effect. The removable PEG layer protects the cytotoxic anti-Fas antibody from premature contact with normal tissues, thus avoiding the unexpected lethal side effect before they reach the tumor site. Due to the high level of MMP expressed by tumor cells inside the tumor tissue, these NPs would shed their PEG layers, resulting in the exposure of anti-Fas antibody to bind the Fas receptor and triggering the apoptosis of tumor cells. Results of Western blot confirmed that these NPs could mimic the function of activated cytotoxic lymphocyte (CTL) to activate the Fas-FasL apoptosis pathway of tumor cells. With the aid of CPT payload, these anti-Fas antibody conjugated NPs achieved a high tumor inhibition in the B16 allograft tumor animal model. The design of these NPs provides a method for delivering cytotoxic ligand to targeting tissue, which may be valuable in cancer therapy.

Multicomponent polymeric nanoparticles enhancing intracellular drug release in cancer cells.

Three kinds of amphiphilic copolymer, that is, poly(ε-caprolactone)-SS-poly(ethylene glycol) (PCL-SS-PEG), poly(ε-caprolactone)-polyethylenimine (PCL-PEI), and poly(ε-caprolactone)-polyethylenimine-folate (PCL-PEI-Fol) were synthesized and self-assembled into surface engineered hybrid nanoparticles (NPs). Morphological studies elucidated the stable, spherical, and uniform sandwich structure of the NPs. PCL-PEI and PCL-SS-PEG segments have introduced pH and reduction responsive characteristics in these NPs, while PCL-PEI-FA copolymers could provide specific targeting capability to cancer cells. The stimuli responsive capabilities of these NPs were carried out. Negative-to-positive charge reversible property, in response to the pH change, was investigated by zeta potential and nuclear magnetic resonance (NMR) measurements. The structure cleavage, due to redox gradient, was studied by dynamic light scattering (DLS) and transmission electron microscopy (TEM). These NPs showed controlled degradation, better drug release, less toxicity, and effective uptake in MCF-7 breast cancer cells. These multifunctional NPs showed promising potential in the treatment of cancer.