Abstract

 This review highlights that Boron Neutron Capture Therapy (BNCT) is currently at a critical stage of clinical translation. Although accelerator-based neutron source technology has matured significantly, the key determinants of therapeutic efficacy remain the tumor selectivity, intratumoral concentration, and microdistribution of boron agents. The article systematically analyzes currently used clinical agents and emerging boron delivery platforms, while discussing existing translational bottlenecks and future development directions.

  

Boron Agents Discussed in This Review

 I. Clinically Established Agents (First / Second Generation)

• BPA (Boronophenylalanine)

• Chemical name: 4-borono-L-phenylalanine

• Class: Amino acid analogue

• Mechanism of action: Transported into tumor cells via LAT1 (L-type amino acid transporter 1)

• Clinical position: The most widely used agent in clinical BNCT

• Strengths: Relatively favorable tumor selectivity with accumulated clinical data

• Limitations: Heterogeneous intratumoral distribution and limited retention time

• BSH (Sodium Borocaptate)

• Chemical name: Na₂B₁₂H₁₁SH

• Class: closo-dodecaborate cluster

• Feature: High boron content (12 boron atoms per molecule)

• Strengths: High boron payload

• Limitations: Lacks active tumor-targeting mechanism and shows lower tumor selectivity compared to BPA

 II. Modified and Third-Generation Boron Agents (Emerging Strategies)

To address challenges such as heterogeneous tumor uptake, limited blood–brain barrier penetration, and tumor microenvironment heterogeneity, the review outlines several research directions:

• Boronated Amino Acid Derivatives

• Structural modification of BPA

• Enhanced transporter affinity

• Prolonged tumor retention time

• Boronated Peptides

• Targeting tumor-specific receptors (e.g., integrins)

• Improved tumor cell specificity

• Capable of incorporating multiple boron clusters

• Boronated Antibodies / Antibody Conjugates

• Antibody-directed delivery (conceptually similar to ADCs)

• High tumor specificity

• Challenges include large molecular size and limited tumor penetration

• Boronated Nanoparticles

• Liposomes

• Polymeric nanoparticles

• Gold nanoparticles

• Advantage: High boron loading capacity

• Challenges: Instability of the EPR effect and translational difficulties

• Carborane-Based Compounds

• High-density boron cage structures

• Conjugatable to small molecules, peptides, or nanoplatforms

• Good chemical stability

• Multifunctional / Theranostic Boron Agents

• Integrated imaging capability (e.g., MRI, PET)

• Therapeutic function (BNCT)

• Aim: Real-time biodistribution monitoring

 Key Technical Considerations

The review identifies several critical challenges in BNCT development:

• Achieving and maintaining sufficient intratumoral boron concentration

• Improving tumor-to-normal tissue (T/N) ratio

• Enhancing intratumoral microdistribution uniformity

• Bridging the translational gap between preclinical research and clinical application

Overall, future boron drug design is expected to focus on:

• Precision targeting

• High boron payload strategies

• Imaging-integrated platforms

• Manufacturability and regulatory feasibility

  Source:
Selg et al., Chemistry – A European Journal (2026)Boron Neutron Capture Therapy at a Crossroads: Translational Gap and Emerging Strategies

 

This content is provided as an academic literature summary for research and informational purposes only and does not constitute medical advice, diagnosis, or treatment recommendations.