Excipient-free prodrug-based three-in-one nanoparticles co-deliver diversified agents to amplify tumor therapy

This study reports the design of a novel excipient-free small molecule prodrug (DEX-ALA)-based nanoparticle (DEX-ALA/DTX) which combines (i) the ability to target dexamethasone (DEX) and docetaxel (DTX) simultaneously to an experimental solid tumor under the natural tumor-targeting properties with (ii) high drugs loading (49.3% DTX, 29.2% DEX, and 21.5% ALA), (iii) high stability (low premature release) in circulation, (iv) stimuli responsive disassembly and release DEX and DTX in tumor, and inducing immunogenic cell death (ICD) for immunotherapy. This concept is based on the inclusion of hydrophobic DTX into nanoparticles constructed by self-assembling of esterase-responsive prodrug of α-linolenic acid (ALA) dexamethasone conjugate. Computational and experimental evidences prove the recapitulation of nanoparticles structure and esterase-responsive release. In tumor compartment, DEX modulates tumor microenvironment, reduces interstitial fluid pressure (IFP) to promote DEX-ALA/DTX nanoparticles accumulating in tumor, and also suppresses inflammation induced tumor progression. DTX exerts its cytotoxicity effect to eliminate tumor cells and induces ICD to produce antitumor immune response. Both systemic administration and peritumoral administration of DEX-ALA/DTX nanoparticles display excellent tumor shrinkage on 4 T1 breast cancer models, but the histology investigation of the tumor biopsies evidences lung metastasis of peritumoral route. These findings give insight in overcoming tumor microenvironment obstacles to promote nanoparticles accumulation and provide a rational strategy to increase antitumor efficiency. This new excipient-free small molecule prodrug based nanotechnology platform is expected to have important applications in cancer therapy.