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Updated: Jun 16, 2025
Polymalic Acid-based Nano Biopolymers for Targeting of Multiple Tumor Markers: An Opportunity for Personalized Medicine?
Published on: June 13, 2014
Design and fabrication of pH-responsive charge-switchable PEG-CDM-PAMAM nanoassemblies to improve tumor therapy
Effat Nekoueifard1, Fatemeh Radmanesh2, Ebrahim Saeedian Moghadam3
1Department of Pharmaceutical Nanotechnology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran; Department of Cell Engineering, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran; Nanotechnology Research Center, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran.
Abstract:
Recent studies have extensively investigated the use of nanocarriers for targeted drug delivery to cancerous tumors, demonstrating promising outcomes. However, their clinical application reveals significant limitations that necessitate substantial revisions for improved efficacy. Addressing issues such as low cell internalization and limited circulation time can improve their therapeutic efficiency. To enhance circulation time, stealth nanocarriers are preferred, while bioadhesive nanoparticles demonstrate higher cell internalization. In this research, pH-responsive PEGylated polyamidoamine (PAMAM) nanoassemblies were prepared. 2-propionic-3-methylmaleic anhydride (CDM) was used as pHe sensitive linkage for the cleavable attachment of poly ethylene glycol (PEG) chains on the surface of PAMAM dendrimers. The obtained PEG-CDM-PAMAM nanoassemblies (PCPNAs) engineered to intelligently address these challenges. The design of PCPNAs enables pH-triggered detachment of PEG chains from the surface at the tumor site, resulting in the exposure of protonated, positively charged residual PAMAM nanoassemblies. Cellular studies revealed enhanced cellular uptake of doxorubicin loaded PCPNAs (DPCPNAs) compared to control PEG-PAMAM nanoassemblies (CPPNAs), pHe-insensitive nanoparticles, with similar structures. Therefore, it presents a solution to one of the problems of current nanocarriers characterized by limited cellular internalization. DPCPNAs not only demonstrate enhanced efficacy in reducing tumor volume in 4 T1 tumor-bearing mice but also elevate cancer cell death and growth suppression compared to free doxorubicin. Moreover, toxicological and histopathological evaluations of vital tissues confirmed the biocompatibility of this drug delivery system. The feature of charge switchability resulted in favorable outcomes for DPCPNAs in both in vitro and in vivo experiments.
Insights
This study developed pH-responsive nanocarriers that improve drug delivery to tumors. The nanocarriers enhance cellular uptake and reduce tumor growth, showing promise for cancer therapy.
Area of Science:
- Biomedical Engineering
- Nanotechnology
- Drug Delivery Systems
Background:
- Current nanocarriers for cancer therapy face limitations like poor cell internalization and short circulation times.
- Stealth nanocarriers improve circulation, while bioadhesive nanoparticles enhance cell uptake, presenting a need for combined strategies.
Purpose of the Study:
- To engineer pH-responsive PEGylated polyamidoamine (PAMAM) nanoassemblies (PCPNAs) for enhanced targeted drug delivery.
- To address limitations of nanocarriers by improving cellular internalization and therapeutic efficacy.
Main Methods:
- Synthesized pH-responsive PEG-CDM-PAMAM nanoassemblies using a pH-sensitive linkage (CDM) for cleavable PEG attachment.
- Loaded doxorubicin into the nanoassemblies (DPCPNAs) and compared their cellular uptake and anti-tumor effects against control nanoparticles (CPPNAs) and free doxorubicin.
- Evaluated in vivo efficacy in 4T1 tumor-bearing mice and assessed biocompatibility through toxicological and histopathological studies.
Main Results:
- DPCPNAs exhibited significantly enhanced cellular uptake compared to CPPNAs.
- DPCPNAs demonstrated superior tumor volume reduction, increased cancer cell death, and growth suppression in vivo.
- Toxicological and histopathological evaluations confirmed the biocompatibility of the DPCPNAs drug delivery system.
Conclusions:
- The developed PCPNAs offer a pH-triggered drug release mechanism, enhancing cellular internalization and therapeutic outcomes.
- This charge-switchable nanocarrier system presents a viable solution for improving cancer drug delivery efficacy and safety.
- The findings highlight the potential of DPCPNAs as an effective and biocompatible nanomedicine for cancer treatment.
