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Antibody-drug conjugates (ADCs) have the following advantages: target specificity; wide therapeutic index; and prolonged circulation half-life. A key limitation of ADCs, however, is the large size (~150 kDa), which markedly slows diffusion through the interstitium of solid tumors and prevents efficient penetration. To address the size issue of ADCs in targeted drug delivery, we developed a HER2-targeting peptide-mertansine conjugate (HER2-TPMC) and conducted a head-to-head comparison with HER2-targeting antibody-mertansine conjugate (HER2-TAMC) as a possible alternative for high-penetration breast cancer therapeutics. As expected, a pharmacokinetic (PK) assay revealed that HER2-TP had lower levels persisting in the circulation after 1 h (~75%) compared to 85% of HER2-targeting antibody (HER2-TA). The cellular cytotoxic effect of HER2-TPMC was similar to HER2-TAMC in the HER2+ BT474 breast cancer cell line, thus demonstrating similar bioactivity of both conjugates. HER2-TPMC not only revealed higher uptake and specificity in in vitro 3D spheroid cultures compared to the parental drug, mertansine, but HER2-TPMC also had a significant retention in the spheroids. This finding was in stark contrast to HER2-TAMC, a large-sized conjugate which was not able to penetrate the spheroid barrier, thus resulting minimal penetration. In vivo tumoral uptake in a BT474 orthotopic model indicated increased tumor uptake and penetration of HER2-TP compared to parental drug and HER2-TAMC. To summarize, we successfully developed a HER2-targeting peptide-mertansine conjugate with specific cellular uptake that resulted in longer retention times in vitro and in vivo. HER2-TPMC (~5 kDa in size) exhibited rapid tissue penetration and enhanced tumoral uptake and retention in vitro and in vivo. Therefore, HER2-TPMC is a reasonable alternative for HER2-positive cancer chemotherapeutics.

T cell infiltration and proliferation in tumor tissues are the main factors that significantly affect the therapeutic outcomes of cancer immunotherapy. Emerging evidence has shown that interferon-gamma (IFNγ) could enhance CXCL9 secretion from macrophages to recruit T cells, but Siglec15 expressed on TAMs can attenuate T cell proliferation. Therefore, targeted regulation of macrophage function could be a promising strategy to enhance cancer immunotherapy via concurrently promoting the infiltration and proliferation of T cells in tumor tissues. We herein developed reduction-responsive nanoparticles (NPs) made with poly (disulfide amide) (PDSA) and lipid-poly (ethylene glycol) (lipid-PEG) for systemic delivery of Siglec15 siRNA (siSiglec15) and IFNγ for enhanced cancer immunotherapy. After intravenous administration, these cargo-loaded could highly accumulate in the tumor tissues and be efficiently internalized by tumor-associated macrophages (TAMs). With the highly concentrated glutathione (GSH) in the cytoplasm to destroy the nanostructure, the loaded IFNγ and siSiglec15 could be rapidly released, which could respectively repolarize macrophage phenotype to enhance CXCL9 secretion for T cell infiltration and silence Siglec15 expression to promote T cell proliferation, leading to significant inhibition of hepatocellular carcinoma (HCC) growth when combining with the immune checkpoint inhibitor. The strategy developed herein could be used as an effective tool to enhance cancer immunotherapy.

CD24, also known as heat-stable protein, is a highly glycosylated glycosylphosphatidylinositol junction membrane protein. CD24 specifically binds sialic-acid-binding Ig-like lectin 10 (Siglec10) on macrophages and serves as a “don’t eat me” signal, thus blocking the phagocytosis of tumor cells by macrophages and triggering tumor immune escape. Blocking the CD24-Siglec10 axis to reprogram the tumor immune microenvironment is a current research hotspot in cancer immunotherapy. Targeting the CD24-Siglec10 axis has received widespread attention, because of the high expression of CD24 on a variety of tumor cells and absence of blood toxicity. Targeting the CD24-Siglec10 axis as a cancer immunotherapy has shown favorable results and progress in preclinical studies. In this review, we summarize the discovery and functions of the CD24-Siglec10 axis, and review the roles and effects of this axis as a novel immune checkpoint in cancer immunotherapy. We also highlight recent advances in nanoparticle-mediated treatments targeting the CD24-Siglec10 axis for enhancing cancer immunotherapy.

Cancer has posed an enormous challenge to human health. To enhance cancer therapy, researchers have constructed the polyprodrug which drug molecules and polymer backbone polymerize to form. In the repeating prodrug units of the polyprodrug, the free drug is connected to the polymer backbone via stimuli-responsive linkages. Polyprodrugs have garnered increasing interest in recent years, due to their promising potential for the protection of drugs, increased drug loading, and systematic release of drugs in reaction to particular triggers. Herein, we present contemporary developments in reduction, pH, hypoxia, reactive oxygen species (ROS), enzymes, and light-responsive polyprodrug within these several decades. We also present the multi-function of polyprodrug triggered by multi-stimulus, before discussing strategies to enhance the targeting, penetration, and uptake of the polyprodrug. Finally, the existing clinical application and prospects of the polyprodrug are proposed.

Chemotherapy has led to many undesirable side effects, as these are toxic drugs that are unable to differentiate between cancer and normal cells. Polyphenols (tea catechins) are an ideal option as alternative chemotherapeutics owing to their inherent anticancer properties, antioxidant properties and being naturally occurring compounds, are deemed safe for consumption. However, without proper administration, the bioavailability of these compounds is low and inefficient. Therefore, proper delivery of these phenolic compounds is vital for cancer therapy. Herein, we analyzed three potential solutions to creating nanoparticle drugs using naturally occurring phenolic compounds (piceatannol (PIC), epigallocatechin gallate hydrophilic (EGCG) and l-epicatechin (EPI)). By using a simple pi-pi stacking mechanism, we utilized boronated PEG (PEG-Br) as an anchor to efficiently load EPI, PIC and EGCG, respectively, to produce three effective phenolic compound-based nanoparticles, which could be delivered safely in systemic circulation, yet detach from its cargo intracellularly to exert its anticancer effect for effective cancer therapy.