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A novel delivery system for cisplatin was constructed based on electrostatics-mediated assemblies of gold nanoclusters and PEGylated cationic peptide (cisplatin@GC-pKs). Encapsulated cisplatin in the as-formed micelle like assemblies was observed to demonstrate improved cellar uptake and enhanced chemotherapeutic efficiency in the cisplatin-resistant lung cancer cells. In vivo assays further confirmed that cisplatin@GC-pKs had profound anti-tumor efficiency due to deep penetration and accumulation of nanoscale cisplatin@GC-pKs via the enhanced permeability and retention (EPR) effect at tumor tissues. The constructed cisplatin@GC-pKs in this work demonstrated enhanced anti-tumor activity for lung cancer therapy, as well as a potential treatment strategy for a variety of cisplatin-resistance related malignancies.

Delivery and accumulation of therapeutic drugs into neoplastic cells distant from tumor vessels is a major challenge for antitumor therapy. Herein, we introduced a de novo peptide, p12 (QGSRRRNTVDDWISRRRALC), to conjugate onto the surface of doxorubicin (DOX) and indocyanine green (ICG) co-encapsulated nanoscale liposomes (pLipo-DOX–ICG). The p12 peptide triggered specific binding to CXC chemokine receptor 4 (CXCR4), leading to enhanced cellular uptake and improved accumulation of pLipo-DOX–ICG in CXCR4-overexpressing cancer cells. Moreover, the introduction of ICG molecules endowed pLipo-DOX–ICG with photothermal-induced structural disruption, which may be helpful for the precise and controllable release of doxorubicin at tumor tissue sites in vivo. With these advantages, the constructed pLipo-DOX–ICG demonstrated active targeting behavior for delivery and release of chemotherapeutic drugs, thereby showing much enhanced metastasis inhibition and antitumor efficacy than either drug-containing liposomes without p12 modification or free drugs in breast cancer bearing mice models. Overall, pLipo-DOX–ICG with low toxicity is expected to be a potential therapeutic agent to improve clinical benefits of breast cancer therapies, as well as treatment of a variety of CXCR4-overexpressing malignancies.

EZH2 is an overexpressed nuclear protein associated with relatively poor survival and chemoresistance in lung cancer. In this study, a nucleus-targeting peptide antagonist EIP103 capable of penetrating cell membrane and nuclear envelope was identified, and has high binding affinity towards EZH2 localized in the nucleus of lung cancer cells. To improve the stability and therapeutic efficacy of EIP103, PEG-PE micelle encapsulated EIP103 (M-EIP103) was successfully conducted. In vitro results indicated that M-EIP103 exhibited better stability, higher intracellular uptake and stronger cytotoxicity than free EIP103 in H446 and A549 cells. Mechanistic studies suggested that M-EIP103 inhibited proliferation by down-regulating the H3K27me3 expression level in cancer cells. In vivo assays further confirmed that both EIP103 and M-EIP103 significantly inhibited lung cancer progression. Notably, enhanced therapeutic efficacy of EIP103 by PEG-PE micelle encapsulation could be identified. The observed anti-tumor activity of EIP103 and M-EIP103 demonstrated a promising therapy to improve clinical treatment of lung cancers as well as other EZH2-overexpressing malignant cancers. This study also illustrates the feasibility of developing targeted delivery of therapeutic peptides to nucleus for cancer therapy.

Lymph node metastases in cancer patients are associated with high aggressiveness, poor prognosis, and short survival time. The chemokine receptor 4 (CXCR4)/stroma derived factor 1α (CXCL12) biological axis plays a critical role in the spread of cancer cells. Designing effective delivery systems that can successfully deliver CXCR4 antagonists to lymph nodes, which are rich in CXCR4-overexpressing cancer cells, for controlling cancer metastasis remain challenging. In this study, we demonstrated that such a challenge may be alleviated by developing nanometer-sized polyethylene glycol-phosphatidylethanolamine (PEG-PE) micelles for the co-delivery of the CXCR4 antagonistic peptide E5 and doxorubicin (M-E5-Dox). This nanomicelle platform enables the preferential accumulation of cargos into lymph nodes and thus can better inhibit cancer metastasis and enhance antitumor efficacy than either free drugs or single drug-loaded micelles in breast cancer-bearing mouse models. Hence, M-E5-Dox is expected to be a potential therapeutic agent that would improve the clinical benefits of breast cancer therapy and treatment of various CXCR4-overexpressing malignancies.

The metastasis of breast cancer is one of the main factors resulting in the high fatality of patients. Although many antagonists have been developed to inhibit the metastasis of breast cancer, their practical application has been limited because of the poor solubility of many chemotherapeutic drugs in the physiological environment. Herein, a complex of E5 peptide antagonist and acetylated PAMAM G5 (P

Liposomes are one of the most widely studied drug carriers due to their relative biocompatibility, lack of immune system stimulation, ability to be cell specific, and serve as a protective drug carrier. Due to several physicochemical properties such as size and charge, liposomes naturally target the phagocytic capabilities of macrophages. In the tumor microenvironment, macrophages strongly influence growth and progression, making them an appealing target for drug delivery. Using the natural capability of liposomes to target macrophages, and the knowledge that material properties can alter cellular responses, this work aims to influence macrophage phenotype with arginine-like surface modified DOPE:DOPC liposomes. These liposomes were incubated with interleukin-4 (IL-4) or lipopolysaccharide (LPS) stimulated macrophages and naïve RAW 264.7 macrophages. Macrophage phenotype was determined through arginase activity, tumor necrosis factor (TNF)-α secretion, and nitrite production. With significant variations in the molecular profiles of each activated cell type, these findings suggest that macrophage responses could be altered with small variations in surface functionality of liposomes.

Misfolding and abnormal aggregation of β-amyloid peptide is associated with the onset and progress of Alzheimer's disease (AD). Therefore, modulating β-amyloid aggregation is critical for the treatment of AD. Herein, we studied the regulatory effects and mechanism of graphene quantum dots (GQDs) on 1–42 β-amyloid (Aβ 1–42 ) aggregation. GQDs displayed significant regulatory effects on the aggregation of Aβ 1–42 peptide as detected by thioflavin T (ThT) assay. Then, the changes of confirmations and structures induced by GQDs on the Aβ 1–42 aggregation were monitored by circular dichroism (CD), dynamic light scattering (DLS) and transmission electron microscope (TEM). The in vitro cytotoxicity experiments further demonstrated the feasibility of GQDs on the regulation of Aβ 1–42 aggregation. Meanwhile, the structural changes of a Aβ 1–42 /GQDs mixture in different pH revealed that electrostatic interaction was the major driving force in the co-assembly process of Aβ 1–42 and GQDs. The proposed mechanism of the regulatory effects of GQDs on the Aβ 1–42 aggregation was also deduced reasonably. This work not only demonstrated the potential feasibility of GQDs as therapeutic drug for AD but also clarified the regulatory mechanism of GQDs on the Aβ 1–42 aggregation.

Characterizations of GQDs by TEM and PL spectrum, and the regulatory effect of GQDs on Aβ aggregation detected by ThT assay

Acute myeloid leukemia (AML) is the most common adult acute leukemia with very low survival rate due to drug resistance and high relapse rate. The C-X-C chemokine receptor 4 (CXCR4) is highly expressed by AML cells, actively mediating chemoresistance and reoccurrence. Herein, a chemically synthesized CXCR4 antagonistic peptide E5 is fabricated to micelle formulation (M-E5) and applied to refractory AML mice, and its therapeutic effects and pharmacokinetics are investigated. Results show that M-E5 can effectively block the surface CXCR4 in leukemic cells separated from bone marrow (BM) and spleen, and inhibit the C-X-C chemokine ligand 12-mediated migration. Subcutaneous administration of M-E5 significantly inhibits the engraftment of leukemic cells in spleen and BM, and mobilizes residue leukemic cells into peripheral blood, reducing organs' burden and significantly prolonging the survival of AML mice. M-E5 can also increase the efficacy of combining regime of homoharringtonine and doxorubicin. Ribonucleic acid sequencing demonstrates that the therapeutic effect is contributed by inhibiting proliferation and enhancing apoptosis and differentiation, all related to the CXCR4 signaling blockade. M-E5 reaches the concentration peak at 2 h after administration with a half-life of 14.5 h in blood. In conclusion, M-E5 is a novel promising therapeutic candidate for refractory AML treatment.

The properties of nanoparticles play an important role in cellular uptake. In this study, we have investigated the effects of 14 arginine modifications on liposome characteristics such as size, zeta potential, the internalization of fluorescein with non-activated macrophages and changes in IC50 values on LPS-activated, IL-4 activated and non-activated macrophages. It is important to determine the influence of surface modifications of particle characteristics on internalization of different macrophages phenotypes. Here we demonstrated that modified surfaces impact particle internalization and this internalization is dependent on macrophage phenotype. Our data revealed that surface modifications alter the zeta potential and negligibly change particle size. Internalization is tunable through alterations in zeta potential and hydrophobicity. These findings demonstrated that targeted drug delivery to macrophages could be achieved by exploiting material parameter.

Correction for ‘Improving the inhibitory effect of CXCR4 peptide antagonist in tumor metastasis with an acetylated PAMAM dendrimer’ by Changliang Liu et al., RSC Adv., 2018, 8, 39948–39956.