Doxorubicin Detoxification in Healthy Organs Improves Tolerability to High Drug Doses for Enhanced Antitumor Therapy

Abstract

With its well-documented toxicity, the use of doxorubicin (Dox) for cancer treatment requires trade-offs between safety and effectiveness. This limited use of Dox also hinders its functionality as an immunogenic cell death inducer, thus impeding its usefulness for immunotherapeutic applications. Here, we develop a biomimetic pseudonucleus nanoparticle (BPN-KP) by enclosing GC-rich DNA within erythrocyte membrane modified with a peptide to selectively target healthy tissue. By localizing treatment to organs susceptible to Dox-mediated toxicity, BPN-KP acts as a decoy that prevents the drug from intercalating into the nuclei of healthy cells. This results in significantly increased tolerance to Dox, thereby enabling the delivery of high drug doses into tumor tissue without detectable toxicity. By lessening the leukodepletive effects normally associated with chemotherapy, dramatic immune activation within the tumor microenvironment was also observed after treatment. In three different murine tumor models, high-dose Dox with BPN-KP pretreatment resulted in significantly prolonged survival, particularly when combined with immune checkpoint blockade therapy. Overall, this study demonstrates how targeted detoxification using biomimetic nanotechnology can help to unlock the full potential of traditional chemotherapeutics.

Biomimetic Nano-Drug Delivery System: An Emerging Platform for Promoting Tumor Treatment

“…More interestingly, peptide-modified CBM-encapsulated GC-rich DNA biomimetic pseudonuclear NPs have been developed to selectively target healthy tissues and serve as bait to prevent doxorubicin (DOX) from embedding into healthy tissues, improving the body’s tolerance to DOX and reducing toxic side effects. 64 NPs with malarial RBCs for tumor-targeted drug delivery have been prepared recently and were inspired by the specific tropism of RBCs infected with malaria, 91 providing conceptual proof for the use of this malaria biomimetic for tumor-targeted drug delivery ( Figure 4 ). Modified nanovesicles (NVs) are a special type of membrane carrier.…”

Ferroptosis Amplifier Remodels Redox Homeostasis for Enhanced Cancer Chemoimmunotherapy

“…From the tumor growth curves, the tumor volume of the PBS group showed a significant increase, and in comparison, DOX and Cu-PDA exhibited partial inhibition of tumor growth (Figure B and Figure S15), whose tumor inhibition rates were 22.7% and 45.2% (Figure S16), respectively. Since DOX is administered systemically, it inevitably causes some damage to normal cells . As seen in Figure C, the body weight of mice treated with DOX slightly decreased during the administration period, while no obvious weight loss was observed in the Cu-PDA and Cu-POX groups.…”

Gelation Behavior and Drug Sustained-Release Properties of a Helix Peptide Organohydrogel with pH Responsiveness

“…Chemotherapy is one of the cancer treatments, among which small molecules such as DOX are the most classic broadspectrum anticancer drugs. 1 Conventional drug delivery tends to release large quantities of the drug directly, resulting in excessive drug concentrations in the blood or tissues at the time of initial administration. These can lead to excessive side effects, such as cardiotoxicity and myelosuppression during clinical treatment.…”

“…Cancer is a major cause of increased mortality worldwide. Chemotherapy is one of the cancer treatments, among which small molecules such as DOX are the most classic broad-spectrum anticancer drugs . Conventional drug delivery tends to release large quantities of the drug directly, resulting in excessive drug concentrations in the blood or tissues at the time of initial administration.…”