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Immunotherapy is an emerging approach for the treatment of solid tumors. Although chemotherapy is generally considered immunosuppressive, specific chemotherapeutic agents can induce tumor immunity. In this study, we developed a targeted, acid-sensitive peptide nanoparticle (DT/Pep1) to deliver doxorubicin (DOX) and triptolide (TPL) to breast cancer cells via the enhanced permeability and retention (EPR) effect and the breast cancer-targeting effect of peptide D8. Compared with administration of the free drugs, treatment with the DT/Pep1 system increased the accumulation of DOX and TPL at the tumor site and achieved deeper penetration into the tumor tissue. In an acidic environment, DT/Pep1 transformed from spherical nanoparticles to aggregates with a high aspect ratio, which successfully extended the retention of the drugs in the tumor cells and bolstered the anticancer effect. In both in vivo and in vitro experiments, DT/Pep1 effectively blocked the cell cycle and induced apoptosis. Importantly, the DT/Pep1 system efficiently suppressed tumor development in mice bearing 4T1 tumors while simultaneously promoting immune system activation. Thus, the results of this study provide a system for breast cancer therapy and offer a novel and promising platform for peptide nanocarrier-based drug delivery., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Temporal persistence is as important for nanocarriers as spatial accuracy. However, because of the insufficient aggreagtion and short retention time of chemotherapy drugs in tumors, their clinical application is greatly limited. A drug delivery approach dependent on the sensitivity to an enzyme present in the microenvironment of the tumor is designed to exhibit different sizes in different sites, achieving enhanced drug permeability and retention to improve tumor nanotherapy efficacy. In this work, we report a small-molecule peptide drug delivery system containing both tumor-targeting groups and enzyme response sites. This system enables the targeted delivery of peptide nanocarriers to tumor cells and a unique response to alkaline phosphatase (ALP) in the tumor microenvironment to activate morphological transformation and drug release. The amphiphilic peptide AYR self-aggregated into a spherical nanoparticle structure after encapsulating the lipid-soluble model drug doxorubicin (DOX) and rapidly converted to nanofibers via the induction of ALP. This morphological transformation toward a high aspect ratio allowed rapid, as well as effective drug release to tumor location while enhancing specific toxicity to tumor cells. Interestingly, this "transformer"-like drug delivery strategy can enhance local drug accumulation and effectively inhibit drug efflux. In vitro along with in vivo experiments further proved that the permeability and retention of antitumor drugs in tumor cells and tissues were significantly enhanced to reduce toxic side effects, and the therapeutic effect was remarkably improved compared with that of nondeformable drug-loaded peptide nanocarriers. The developed AYR nanoparticles with the ability to undergo morphological transformation in situ can improve local drug aggregation and retention time at the tumor site. Our findings provide a new and simple method for nanocarrier morphology transformation in novel cancer treatments.

Liposomes have been widely used as drug carriers in both biomedical research and for clinical applications, allowing the stabilisation of therapeutic compounds and overcoming obstacles to cellular and tissue uptake. However, liposomes still have low targeting efficiency, resulting in insufficient killing of tumour cells and unnecessary damage to normal cells. In this study, glycyrrhetinic acid (GA) and peanut agglutinin (PNA) were used as ligands to prepare dual-ligand-modified doxorubicin-loaded liposomes (DOX-GA/PNA-Lips) to enhance the targeting accuracy and efficacy of drug delivery against malignant liver cancer. PNA and GA modification enhanced the binding ability of liposomes to liver cancer cells, leading to excellent tissue and cell targeting of DOX-GA/PNA-Lips. DOX-GA/PNA-Lips showed an effective anti-tumour effect in vivo and in vitro, with its targeted delivery facilitating attenuation of the toxic side effects of DOX. These results demonstrated that dual-ligand-modified liposomes may provide an effective strategy for the treatment of hepatocellular carcinoma., (Copyright © 2020 Elsevier B.V. All rights reserved.)

The geometry of nanoparticles plays an important role in their performance as drug carriers. However, the pH-triggered geometrical shape switching of a cationic peptide consisting of isoleucine and lysine is seldom reported. In this work, we designed a cationic peptide with acid reactivity that can be loaded with the poorly soluble antitumor drug (doxorubicin (DOX)) to enhance tumor cell uptake and drug delivery. In a weakly acidic environment, a large portion of random coil structures formed, which subsequently led to nanoparticle destruction and rapid DOX release. In vitro studies demonstrated that this cationic peptide exhibits low toxicity to normal cells. The amount of DOX-encapsulating peptide nanoparticles taken up by tumor cells was greater than that taken up by normal cells. Our results indicated that the use of a weakly acidic microenvironment to induce geometric shape switching in drug-loaded peptide nanoparticles should be a promising strategy for antitumor drug delivery., Competing Interests: Declaration of Competing Interest The authors declare no competing financial interest., (Copyright © 2020 Elsevier B.V. All rights reserved.)

A novel GHH copolymer was synthesized using hyaluronic acid modified with glycyrrhetinic acid and L‑histidine (His), and doxorubicin‑loaded GHH nanoparticles (DOX/GHH) were prepared for liver‑targeted drug delivery and pH‑responsive drug release. In the present study, GHH nanoparticles were characterized, and their pH‑responsive behaviors were evaluated at different pH levels. The antitumor effect of the DOX/GHH nanoparticles was investigated in vitro and in vivo. Results showed that the DOX/GHH nanoparticles were spherical, and the particle sizes ranged from 238.1 to 156.7 nm with an increase in the degree of substitution of His. The GHH nanoparticles were obviously internalized into human hepatoblastoma cells. In vitro cytotoxicity assay results showed that the DOX/GHH nanoparticles exhibited a dose‑dependent antitumor effect. Compared with free DOX, the DOX/GHH nanoparticles displayed higher antitumor efficacy. These results indicate that GHH nanoparticles could be a promising nano‑delivery carrier of hydrophobic drugs for liver‑targeted therapy.

[Display omitted] • The deformable drug-loaded peptide nanocarriers DM/Pep1 targeted breast cancer cells. • DM/Pep1 underwent morphological transformation to prolong the retention time of the encapsulated drugs. • DM/Pep1 upregulated CD4, induced calreticulin exposure, downregulated PD-L1 and enhanced antitumor immune response. Insufficient drug accumulation at tumor sites is one of the key factors leading to treatment failure in breast cancer (BC), and developing a chemotherapeutic drug delivery system that can improve the immune microenvironment to expand the benefits of immunochemotherapy for BC remains a challenge. To increase the efficacy of BC treatment by extending drug retention at the tumor site, we developed a pH-responsive peptide modified with the PHSCN peptide sequence (Pep1) that self-assembles to form spherical DM/Pep1 nanoparticles after encapsulating doxorubicin (DOX) and metformin (MET). In the acidic tumor microenvironment, spherical nanocarriers transform into aggregates with a high aspect ratio, facilitating DOX and MET release for combined chemotherapy and immunomodulation. In cellular experiments, this construct provided prolonged drug retention in BC cells. In a subcutaneous tumor mouse model, the DM/Pep1 nanoparticles exhibited a superior tumor inhibition effect compared to that of free DOX/MET. The DM/Pep1 nanocomplex upregulated CD4, induced calreticulin (CRT) exposure, downregulated PD-L1, and enhanced the MET-mediated antitumor immune response. The use of this pH-responsive peptide nanocarrier system with morphological transformation offers a promising strategy for BC therapy. [ABSTRACT FROM AUTHOR]