Strategic Optimization of Nanoparticle Characteristics to Enhance Tumor Targeting and Doxorubicin Delivery.

Background: Doxorubicin (Dox) is a potent anticancer agent; however, its therapeutic efficacy is constrained by a narrow therapeutic index, resulting in nonselective cardiotoxicity and nephrotoxicity. To improve its specificity and therapeutic efficacy, multivalent targeting strategies are being developed.

Methods: A chimeric polypeptide consisting of an elastin-like polypeptides (ELP) copolymer with a repeating IL-4 receptor-specific targeting peptide, AP-1, and a (GGCGSCGSC)₂ sequence encoding 6 cysteine residues (C6) at the carboxyl-terminus for Dox conjugation was designed. Several AP1-ELPs of varying molecular sizes and structures, ranging from unimers to micelle-forming polymers, were characterized to evaluate their influence on Dox delivery and tumor inhibition.

Results: Conjugating Dox to the C6 via an acid-labile linker induced self-assembly into micelle-like structures at body temperature. The size of these multivalent constructs significantly influenced their tumor penetration and overall therapeutic outcomes. High molecular weight, micelle-forming AP1-ELP constructs demonstrated faster tumor entry and enhanced inhibition compared to lower molecular weight linear AP1-ELPs. Tumor uptake of Dox was five times greater than that of free drug and twice that of low molecular weight, linear AP1-ELPs. Furthermore, systemic administration of these high molecular weight constructs effectively inhibited tumor growth in breast carcinoma xenograft models without inducing specific organ toxicity.

Conclusion: Outperforming free Dox, high molecular weight micelle-forming AP1-ELP constructs achieve superior tumor targeting and efficacy with minimal toxicity, highlighting their potential as safer and more promising carriers for targeted drug delivery.