Advanced biomaterials for cancer immunotherapy.

Immunotherapy, as a powerful strategy for cancer treatment, has achieved tremendous efficacy in clinical trials. Despite these advancements, there is much to do in terms of enhancing therapeutic benefits and decreasing the side effects of cancer immunotherapy. Advanced nanobiomaterials, including liposomes, polymers, and silica, play a vital role in the codelivery of drugs and immunomodulators. These nanobiomaterial-based delivery systems could effectively promote antitumor immune responses and simultaneously reduce toxic adverse effects. Furthermore, nanobiomaterials may also combine with each other or with traditional drugs via different mechanisms, thus giving rise to more accurate and efficient tumor treatment. Here, an overview of the latest advancement in these nanobiomaterials used for cancer immunotherapy is given, describing outstanding systems, including lipid-based nanoparticles, polymer-based scaffolds or micelles, inorganic nanosystems, and others.

Tumor-Targeting Anti-MicroRNA-155 Delivery Based on Biodegradable Poly(ester amine) and Hyaluronic Acid Shielding for Lung Cancer Therapy.

Anti-microRNA-155 (anti-miR-155), an oligonucleotide with a complimentary sequence to microRNA-155, holds great promise for lung cancer therapy, and thus some cationic materials have been used to deliver anti-miR-155 into lung tumors. Although the gene delivery capacity in vitro was favorable, the application in vivo was limited by rapid removal and significant cytotoxicity, which were mainly caused by the positive charge of the gene complexes. Therefore, it was necessary to develop a novel carrier to decrease the positive charge and increase the gene delivery capacity into the tumor site. In this paper, biodegradable poly(ester amine) (PEA) was used to condense anti-miR-155 into PEA/anti-miR-155 complexes, and natural anionic polysaccharide hyaluronic acid (HA) was modified with a lung tumor cell targeting peptide and then coated on the surface of gene complexes. The formed hyaluronic acid shielding, PEA/anti-miR-155/HA-peptide complexes were monodispersed, and the particle size and zeta potential were 362.7 nm and -10.17 mV, respectively. In addition, the PEA/anti-miR-155/HA-peptide complexes had good biocompatibility and stability in vitro, and the lung tumor growth inhibitions of PEA/anti-miR-155/HA-peptide in vitro and in vivo were also excellent. The PEA/anti-miR-155/HA-peptide complexes play an active role in tumor growth inhibition and could be useful for lung cancer therapy.

Synthesis and Application of a Novel Gene Delivery Vector for Non-Small-Cell Lung Cancer Therapy.

Human Wnt inhibitory factor-1 (hWIF-1), as an anti-oncogene, holds great promise for non-small-cell lung cancer (NSCLC) therapy. However, the clinical application of hWIF-1 in cancer therapy is limited by elimination and degradation of free hWIF-1 in vivo. Therefore, it is necessary to develop safe and effective gene delivery vectors for hWIF-1 delivery in vivo. In this paper, we synthesized a novel polyethylenimine (PEI) derivative PEI-SP5-2 (PES) based on branched PEI1800 and NSCLC-targeting peptide SP5-2 to deliver hWIF-1 for NSCLC therapy. PES had excellent gene delivery capacity, and the transfection efficiency reached 50.02% ± 4.75% in A549 cell lines when the weight ratio of PES/gene was 100. Besides, the PES/gene particles were monodispersed, and the hydrodynamic diameter and zeta potential were 47.55 nm and 24.9 mV, respectively. In addition, PES/hWIF-1 complexes could inhibit the tumor growth in vitro and in vivo when it was used for non-small-cell lung cancer therapy. We concluded that PES would be promising as a novel gene delivery vector, and PES/hWIF-1 complexes inhibited the tumor growth and showed potential for non-small-cell lung cancer therapy.

Negative regulation of cationic nanoparticle-induced inflammatory toxicity through the increased production of prostaglandin E2 via mitochondrial DNA-activated Ly6C+ monocytes.

Rationale: Cationic nanocarriers present with well-known toxicities, including inflammatory toxicity, which limit their clinical application. How the cationic nanocarrier-induced inflammatory response is negatively regulated is unknown. Herein, we found that following a sublethal dose of cationic nanocarriers, the induced inflammatory response is characterized by early neutrophil infiltration and spontaneous resolution within 1 week. Methods: C57BL/6 mice were intravenously injected with a dosage of 1-100 mg/kg cationic DOTAP liposomes as well as other cationic materials. Cell necrosis was detected by flow cytometry. Release of mitochondrial DNA was quantified by qPCR via Taqman probes. Signal proteins were detected by Western blotting. PGE2 production in the supernatant was quantitated using an enzyme immunoassay (EIA). The infiltrated inflammatory cells were observed in WT mice, Ccr2-/- mice, Sting-/- mice and Tlr9-/- mice. Results: The early stage (24-48 h) inflammatory neutrophil infiltration was followed by an increasing percentage of monocytes; and, compared with WT mice, Ccr2-/- mice presented with more severe pulmonary inflammation. A previously uncharacterized population of regulatory monocytes expressing both inflammatory and immunosuppressive cytokines was identified in this model. The alteration in monocyte phenotype was directly induced by mtDNA release from cationic nanocarrier-induced necrotic cells via a STING- or TLR9-dependent pathway. Neutrophil activation was specifically inhibited by PGE2 from Ly6C+ inflammatory monocytes, and intravenous injections of dual-phenotype monocytes beneficially modified the immune response; this inhibitory effect was abolished after treatment with indomethacin. Moreover, we provide clear evidence that mitochondrial DNA activated Ly6C+ monocytes and increased PGE2 production through TLR9- or STING-mediated MAPK-NF-κB-COX2 pathways. Conclusion: Our findings suggest that Ly6C+ monocytes and mtDNA-induced Ly6C+ monocyte PGE2 production may be part of a feedback mechanism that contributes to the resolution of cationic nanocarrier-induced inflammatory toxicity and may have important implications for understanding nanoparticle biocompatibility and designing better, safer drug delivery systems.

Novel Approach of Using Near-Infrared Responsive PEGylated Gold Nanorod Coated Poly(l-lactide) Microneedles to Enhance the Antitumor Efficiency of Docetaxel-Loaded MPEG-PDLLA Micelles for Treating an A431 Tumor.

The combination of chemotherapy and photothermal therapy (PTT) plays a significant role in synergistic tumor therapy. However, a high dosage of chemotherapy drugs or photothermal agents may cause series side effects. To overcome these challenges, we designed a near-infrared (NIR) responsive PEGylated gold nanorod (GNR-PEG) coated poly(l-lactide) microneedle (PLLA MN) system (GNR-PEG@MN) to enhance antitumor efficiency of docetaxel-loaded MPEG-PDLLA (MPEG-PDLLA-DTX) micelles for treating an A431 tumor. The as-made GNR-PEG@MNs contained only 31.83 ± 1.22 µg of GNR-PEG per patch and exhibited excellent heating efficacy both in vitro and in vivo. Meanwhile, GNR-PEG@MN with the height of 480 µm had good skin insertion ability and was harmless to the skin. On the other hand, GNR-PEG@MN had good heating transfer ability in vivo, and the tumor sites could reach 50 °C within 5 min. In comparison with chemotherapy and PTT alone, the combination of low dosage MPEG-PDLLA-DTX micelles (5 mg/kg) and GNR-PEG@MNs completely eradicated the A431 tumor without recurrence in vivo, demonstrating a remarkable synergetic effect. Hence, GNR-PEG@MN could be a promising carrier to enhance the antitumor effect of MPEG-PDLLA-DTX micelles for treating superficial tumors and is expected to have a great potential in clinical translation for human epidermoid cancer therapy.

A novel gene delivery composite system based on biodegradable folate-poly (ester amine) polymer and thermosensitive hydrogel for sustained gene release.

Local anti-oncogene delivery providing high local concentration of gene, increasing antitumor effect and decreasing systemic side effects is currently attracting interest in cancer therapy. In this paper, a novel local sustained anti-oncogene delivery system, PECE thermoresponsive hydrogel containing folate-poly (ester amine) (FA-PEA) polymer/DNA (tumor suppressor) complexes, is demonstrated. First, a tumor-targeted biodegradable folate-poly (ester amine) (FA-PEA) polymer based on low-molecular-weight polyethyleneimine (PEI) was synthesized and characterized, and the application for targeted gene delivery was investigated. The polymer had slight cytotoxicity and high transfection efficiency in vitro compared with PEI 25k, which indicated that FA-PEA was a potential vector for targeted gene delivery. Meanwhile, we successfully prepared a thermoresponsive PECE hydrogel composite containing FA-PEA/DNA complexes which could contain the genes and slowly release the genes into cells. We concluded the folate-poly (ester amine) (FA-PEA) polymer would be useful for targeted gene delivery, and the novel gene delivery composite based on biodegradable folate-poly (ester amine) polymer and thermosensitive PECE hydrogel showed potential for sustained gene release.