A PD‐L1 Antibody‐Conjugated PAMAM Dendrimer Nanosystem for Simultaneously Inhibiting Glycolysis and Promoting Immune Response in Fighting Breast Cancer

Abstract

Breast cancer is the most frequent malignancy affecting women, yet current therapeutic strategies remain ineffective for patients with late‐stage or metastatic disease. We report here an effective strategy for treating metastatic breast cancer. Specifically, we established a self‐assembling dendrimer nanosystem decorated with an anti‐PD‐L1 antibody for delivering a small interfering RNA (siRNA) to target PDK1, a protein kinase involved in cancer metabolism and metastasis. This nanosystem (named PPD) was designed to target PD‐L1 for cancer specific delivery of the siRNA to inhibit PDK1 (named siPDK1) and modulate cancer metabolism while promoting PD‐1/PD‐L1 pathway‐based immunotherapy. Indeed, PPD effectively protected siPDK1 from degradation and supported its specific delivery to cancer cells for downregulating PDK1 expression. This resulted in simultaneous inhibition of PDK1‐induced glycolysis and the PD‐1/PD‐L1 pathway‐related immune response, leading to potent inhibition of tumor growth and metastasis without any notable toxicity in tumor‐bearing mouse models. Collectively, these results highlight the potential use of PPD as an effective and safe tumor‐targeting therapy for breast cancer. This study constitutes a successful proof of principle exploiting the intrinsic features of tumor microenvironment and metabolism alongside unique self‐assembling dendrimer platform to achieve specific tumor targeting and siRNA‐based gene silencing in combined and precision cancer therapy.This article is protected by copyright. All rights reserved

In Vivo Applications of Dendrimers: A Step toward the Future of Nanoparticle-Mediated Therapeutics

“…The perspectives for the use of dendrimer-based systems as nanomedicines [ 43 ], biological adhesives [ 44 ], imaging agents [ 45 ], and in gene therapy [ 46 ] are all very promising. Dendrimers can be also used as vectors for the delivery of genes [ 47 ], nucleic acids [ 48 ], and drugs [ 49 ]. Moreover, research is currently underway to use dendrimers as adjuvants in vaccines [ 50 ] based on evidence that nanoparticles protect drugs from biodegradation, prolong their half-life in blood, improve their solubility, and provide targeted delivery [ 51 ].…”

Charting new frontiers: Co-inhibitory immune checkpoint proteins in therapeutics, biomarkers, and drug delivery systems in cancer care

“… 4T1 tumor [79] Dendrimer siPDK1-PD-L1 mAb-dendrimer complex (PPD) SiPDK1 and aPDL1 This study developed a dendrimer nanosystem called PPD, decorated with a aPDL1, to deliver siRNA targeting PDK1, a kinase influencing cancer metabolism and metastasis; this system concurrently inhibits PDK1-induced glycolysis and enhances PD-1/PD-L1 pathway-based immunotherapy, resulting in pronounced tumor growth and metastasis suppression in mouse models, illustrating its potential for targeted breast cancer therapy by leveraging tumor environment features and siRNA-based gene silencing. 4T1 tumor [80] Micelle sAMPc aPDL1 and ZnPc A pH/enzyme dual-sensitive nanodrug was crafted, hierarchically integrating a photosensitizer and aPDL1; this design leverages the tumor's unique environment to sequentially shed its PEG coating and release the aPDL1, followed by tumor cell-targeted delivery and light-triggered PDT, synergistically enhancing immuno-PDT and diminishing aPDL1’s adverse effects. B16F10 melanoma [81] sAMcP aPD1 and PTX A micellar nanocarrier, sensitive to pH and matrix metalloproteinase, enables sequential release of aPD1 and paclitaxel in tumors, with the former blocking the immune escape amplified by the latter, and its sheddable PEG layer ensures targeted tumor accumulation, exemplifying potent chemoimmunotherapy in a melanoma mouse model.…”

“…In a pivotal study, Zhang and colleagues formulated a self-assembled dendritic polymer nanosystem, augmented with an anti-PD-L1 antibody, for delivering small interfering RNA (siRNA) targeting 3-phosphatidylinositol-dependent protein kinase-1 (PDK1) [80] . The resultant siPDK1-PD-L1mAb-dendritic polymer complexes, referred to as PPDs, demonstrated enhanced protection of siPDK1 against degradation.…”