Biodegradable PEG-PCL Nanoparticles for Co-delivery of MUC1 Inhibitor and Doxorubicin for the Confinement of
Akanksha Behl1, Subhash Solanki2, Shravan K Paswan3
1Centre for Biotechnology, M.D. University, Rohtak, Haryana 124 001 India.
Abstract:
Combating triple-negative breast cancer (TNBC) is still a problem, despite the development of numerous drug delivery approaches. Mucin1 (MUC1), a glycoprotein linked to chemo-resistance and progressive malignancy, is unregulated in TNBC. GO-201, a MUC1 peptide inhibitor that impairs MUC1 activity, promotes necrotic cell death by binding to the MUC1-C unit. The current study deals with the synthesis and development of a novel nano-formulation (DM-PEG-PCL NPs) comprising of polyethylene glycol-polycaprolactone (PEG-PCL) polymer loaded with MUC1 inhibitor and an effective anticancer drug, doxorubicin (DOX). The DOX and MUC1 loaded nanoparticles were fully characterized, and their different physicochemical properties, viz. size, shape, surface charge, entrapment efficiencies, release behavior, etc., were determined. With IC50 values of 5.8 and 2.4 nm on breast cancer cell lines, accordingly, and a combination index (CI) of < 1.0, DM-PEG-PCL NPs displayed enhanced toxicity towards breast cancer cells (MCF-7 and MDA-MB-231) than DOX-PEG-PCL and MUC1i-PEG-PCL nanoparticles. Fluorescence microscopy analysis revealed DOX localization in the nucleus and MUC1 inhibitor in the mitochondria. Further, DM-PEG-PCL NPs treated breast cancer cells showed increased mitochondrial damage with enhancement in caspase-3 expression and reduction in Bcl-2 expression.In vivo evaluation using Ehrlich Ascites Carcinoma bearing mice explicitly stated that DM-PEG-PCL NPs therapy minimized tumor growth relative to control treatment. Further, acute toxicity studies did not reveal any adverse effects on organs and their functions, as no mortalities were observed. The current research reports for the first time the synergistic approach of combination entrapment of a clinical chemotherapeutic (DOX) and an anticancer peptide (MUC1 inhibitor) encased in a diblock PEG-PCL copolymer. Incorporating both DOX and MUC1 inhibitors in PEG-PCL NPs in the designed nanoformulation has provided chances and insights for treating triple-negative breast tumors. Our controlled delivery technology is biodegradable, non-toxic, and anti-multidrug-resistant. In addition, this tailored smart nanoformulation has been particularly effective in the therapy of triple-negative breast cancer.
Supplementary Information:
The online version contains supplementary material available at 10.1007/s10924-022-02654-4.
Insights
This study developed novel nanoparticles combining doxorubicin and a MUC1 inhibitor to treat triple-negative breast cancer (TNBC). The formulation showed enhanced efficacy and reduced tumor growth in vivo with no observed toxicity.
Area of Science:
- Biomedical Engineering
- Nanotechnology
- Oncology
Background:
- Triple-negative breast cancer (TNBC) remains challenging due to chemo-resistance.
- Mucin1 (MUC1) is upregulated in TNBC and associated with poor prognosis.
- Existing treatments have limitations in efficacy and delivery.
Purpose of the Study:
- To synthesize and characterize novel dual-drug loaded nanoparticles (DM-PEG-PCL NPs) for TNBC therapy.
- To evaluate the synergistic anti-cancer effects of doxorubicin (DOX) and a MUC1 inhibitor.
- To assess the in vitro and in vivo efficacy and safety of the developed nanoformulation.
Main Methods:
- Synthesis and physicochemical characterization of DM-PEG-PCL NPs.
- In vitro cytotoxicity assays on breast cancer cell lines (MCF-7, MDA-MB-231).
- Cellular uptake and mechanism of action studies (fluorescence microscopy, apoptosis markers).
- In vivo anti-tumor efficacy studies in a mouse model (Ehrlich Ascites Carcinoma).
- Acute toxicity assessment in mice.
Main Results:
- DM-PEG-PCL NPs demonstrated enhanced cytotoxicity against breast cancer cells compared to single-drug nanoparticles.
- Combination index (CI) < 1.0 indicated synergistic anti-cancer activity.
- DOX localized in the nucleus and MUC1 inhibitor in mitochondria, inducing apoptosis.
- In vivo studies showed significant tumor growth inhibition with DM-PEG-PCL NPs.
- No adverse effects or mortality were observed in acute toxicity studies.
Conclusions:
- The developed DM-PEG-PCL NPs offer a promising synergistic approach for TNBC treatment.
- This nanoformulation effectively delivers both a chemotherapeutic and a targeted inhibitor.
- The biodegradable and non-toxic nature of the nanoparticles supports their potential clinical translation for TNBC therapy.
