Novel Dual Strategy Based on EPR/AT for Optimizing Therapeutic Effect by Improving Drug Delivery System
Long Chen1,2, Xiang Deng1,2,3, Qian Shen1,2,3
1The Second Affiliated Hospital of Chengdu Medical College, Nuclear Industry 416 Hospital Chengdu, Sichuan, 610000, People's Republic of China.
Abstract:
The clinical advancement of cancer nanomedicine is significantly hindered by its limited accumulation in tumors, a key factor behind the frequent failure of nanodrugs in clinical trials. The effectiveness of these nanodrugs is closely tied to their route of administration, whether oral, transdermal, intravenous, or intracerebral, as each path presents unique physiological barriers that impede bioavailability and precise tumor targeting. Among the major causes of poor accumulation are rapid clearance by the mononuclear phagocyte system, opsonization accompanied by protein corona formation, renal filtration, and the abnormal, heterogeneous nature of tumor vasculature that restricts passive targeting via the enhanced permeability and retention (EPR) effect. In response, active targeting (AT) strategies have been widely explored, including surface modification with ligands, antibodies, or aptamers designed to bind specifically to overexpressed receptors on cancer cells or blood vessels. Despite these efforts, challenges such as the dense extracellular matrix, elevated interstitial fluid pressure, and the notable inconsistency of the EPR effect between animal models and human patients continue to limit therapeutic penetration. This review offers a systematic examination of nanodrug delivery pathways and the reasons behind their inadequate accumulation, highlighting the potential of both active targeting and combined passive-active strategies to enhance tumor-specific delivery. Overcoming these biological barriers through refined nano-design is crucial for developing the next generation of nanomedicines with improved tumor accumulation and treatment outcomes.
Insights
Limited tumor accumulation hinders cancer nanomedicine. Strategies like active targeting (AT) aim to improve nanodrug delivery by overcoming biological barriers for better cancer treatment outcomes.
Area of Science:
- Biomedical Engineering
- Nanotechnology
- Oncology
Background:
- Clinical advancement of cancer nanomedicine is impeded by poor tumor accumulation, a primary cause of nanodrug failure in trials.
- Various administration routes (oral, transdermal, intravenous, intracerebral) face physiological barriers affecting bioavailability and tumor targeting.
- Key challenges include mononuclear phagocyte system clearance, protein corona formation, renal filtration, and heterogeneous tumor vasculature limiting the enhanced permeability and retention (EPR) effect.
Purpose of the Study:
- To systematically review nanodrug delivery pathways and identify reasons for inadequate tumor accumulation.
- To highlight the potential of active targeting (AT) and combined passive-active strategies for enhanced tumor-specific delivery.
- To emphasize the need for refined nano-design to overcome biological barriers for improved nanomedicine efficacy.
Main Methods:
- Review of existing literature on nanodrug delivery systems and tumor targeting strategies.
- Analysis of physiological barriers impacting nanodrug accumulation and therapeutic efficacy.
- Examination of active targeting approaches, including ligand, antibody, and aptamer modifications.
- Evaluation of combined passive and active targeting strategies.
Main Results:
- Limited nanodrug accumulation in tumors is a major obstacle in clinical translation.
- Physiological barriers and the inconsistent EPR effect significantly restrict passive tumor targeting.
- Active targeting strategies show promise but face challenges like dense extracellular matrix and high interstitial fluid pressure.
- Combined passive-active targeting approaches offer potential for improved tumor penetration.
Conclusions:
- Overcoming biological barriers is critical for successful cancer nanomedicine.
- Refined nano-design and strategic targeting are essential for enhancing tumor accumulation.
- Future nanomedicines require improved strategies to achieve better therapeutic outcomes in cancer treatment.
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