Synergistic Disruption of Metabolic Homeostasis through Hyperbranched Poly(ethylene glycol) Conjugates as Nanotherapeutics to Constrain Cancer Growth

Abstract

with nanoparticles (NPs) has emerged as a promising strategy for maximizing the effectiveness of combination therapies by simultaneously regulating various pathways. [2] Despite some advancements, different types of pharmaceuticals have significantly diverse physicochemical properties, and thus it remains a major challenge to achieving efficient co-loading of different pharmaceuticals at a defined ratio in a single nanoparticle. Additionally, characterizations of their pharmacological and physicochemical properties are typically conducted using physical, chemical, and biological analyses. [3] However, without molecular or atomic-level information, it is difficult to design, evaluate, and optimize a co-delivery nanoformulation to achieve better and safer therapeutic/prognostic effects. Simulations with an increased computational capacity have been developed to accurately describe atomic or molecular interactions in nanomedicines, enabling bottomup approaches of designing nanoparticles for combination therapy. [4] So far, there has been no report of the de novo design Combination therapy is a promising approach for effective treatment of tumors through synergistically regulating pathways. However, the synergistic effect is limited, likely by uncontrolled co-delivery of different therapeutic payloads in a single nanoparticle. Herein, a combination nanotherapeutic is developed by using two amphiphilic conjugates, hyperbranched poly(ethylene glycol)-pyropheophorbide-a (Ppa) (HP-P) and hyperbranched poly(ethylene glycol)-doxorubicin (DOX) (HP-D) to construct co-assembly nanoparticles (HP-PD NPs) for controllably co-loading and co-delivering Ppa and DOX. In vitro and in vivo antitumor studies confirm the synergistic effect of photodynamic therapy and chemotherapy from HP-PD NPs. Metabolic variations reveal that tumor suppression is associated with disruption of metabolic homeostasis, leading to reduced protein translation. This study uncovers the manipulation of metabolic changes in tumor cells through disruption of cellular homeostasis using HP-PD NPs and provides a new insight into the rational design of synergistic nanotherapeutics for combination therapy.

Immunogenic Cell Death Activates the Tumor Immune Microenvironment to Boost the Immunotherapy Efficiency

“…This is known as the “Warburg effect,” which results in physiochemical differences of the tumor microenvironment between cancer and normal cells, such as a low pH, a high level of glutathione (GSH) and rich enzymes. [ 68 ] The differences can be used to fine tune the release of therapeutic agents from NDDSs. [ 69 ] Acid‐sensitive bonds in NDDSs including hydrazone, thiopropionate, imine, acetal, and ketone can be cleaved under tumor acidic conditions to responsively release cargos.…”

Reactive oxygen species-upregulating nanomedicines towards enhanced cancer therapy

“…Pan et al proposed the use of hyperbranched PEG conjugate hybrid NPs for controlled drug loading and self-assembly. 341 The optimal NPs were obtained by tuning the feeding ratio of hyperbranched PEG-Ppa conjugate to hyperbranched PEG-DOX conjugate. Importantly, the synergistic cancer therapy is attributed to the disruption of metabolic homeostasis and reduced protein translation.…”

Recent advances in photothermal therapy-based multifunctional nanoplatforms for breast cancer

“…Photodynamic therapy (PDT) has been demonstrated as a minimally invasive method to treat various types of cancer, including breast cancer, melanoma, and lung cancer ( Tang et al, 2021 ; Ding et al, 2022 ; Jia et al, 2022 ; Obaid et al, 2022 ; Pan et al, 2022 ; Zhang et al, 2022 ). The photosensitizers can be activated under a light source to generate reactive oxygen species (ROS) to kill cancer cells.…”