Researchers from Tehran University of Medical Sciences, in collaboration with scientists from the Royan Institute, the University of Science and Culture, and De Montfort University (UK), have developed advanced smart nanocarriers capable of dynamically changing their size and surface charge to deliver the chemotherapy drug doxorubicin (DOX) deep into tumor tissues.
According to the Report, this technology enhances both deep tumor tissue penetration and cellular uptake of the drug, while simultaneously preventing the destructive effects of the acidic extracellular tumor microenvironment. The developed PAMAM-based nanocarriers, featuring switchable size and surface charge, promise more efficient therapies, reduced drug resistance, and minimal damage to healthy tissues, opening new pathways for low-relapse cancer treatments. Experimental results demonstrated that these nanocarriers not only protect the drug but also exhibit significant antitumor activity.
In cancer therapy, one of the major challenges is enabling drugs to penetrate deeply into tumor tissues and be effectively absorbed by cells. Many chemotherapeutic drugs, even upon reaching the tumor, fail to access its inner regions or become inactivated in the acidic extracellular environment. To address this, researchers have sought to design nanocarriers that can adapt their size and surface charge in response to environmental conditions while facilitating intracellular drug delivery.
In this context, the Tehran research team and their international collaborators successfully developed size- and charge-switchable PAMAM megamers (SChPMs) designed for doxorubicin delivery. These nanocarriers were constructed by linking PAMAM dendrimers through pH-sensitive bonds and coating them with PEG. At neutral pH (7.4), the particles measured around 100 nm in diameter with a surface charge of +0.75 mV, whereas in the acidic extracellular tumor environment (pH 6.5), their size decreased to 15 nm and the surface charge increased to +6.7 mV.
These adaptive changes enabled deeper penetration into 3D tumor spheroids and more efficient cellular uptake. Moreover, the nanocarriers protected the drug from deactivation in the acidic environment and markedly reduced cellular resistance to anthracycline drugs. Animal studies using 4T1 tumor-bearing mice confirmed the nanocarriers’ strong antitumor effects with minimal tissue damage.
The researchers emphasized the importance of integrating experimental and molecular simulation approaches, noting that the design of such nanocarriers not only enhances therapeutic efficacy but also paves the way for clinical translation of similar technologies in treating various cancers. Additionally, the ability of the particles to alter their size and charge significantly improved cellular endocytosis, facilitating penetration into deeper tumor regions.
The PAMAM-based nanocarriers effectively delivered doxorubicin into the inner tumor regions and prevented its inactivation under acidic conditions, a major advantage over conventional drug formulations. This feature represents a key step toward targeted, side-effect-reduced cancer therapies.
This study exemplifies a successful innovation in nanocarrier design, leveraging tumor microenvironmental cues for intelligent drug delivery. By switching their size and surface charge, the PAMAM nanocarriers address two major challenges in cancer therapy: deep penetration and efficient cellular uptake. These findings open new avenues for clinical research, targeted drug design, and nanotechnology-based cancer treatments, promising a new generation of highly effective anticancer drugs with minimal harm to healthy tissues.
The results of this project have been published in the Journal of Controlled Release under the title: “Switchable PAMAM Megamers for Deep Tumor Penetration and Enhanced Cell Uptake.”