Apoptotic body–mediated intercellular delivery for enhanced drug penetration and whole tumor destruction

Abstract

Chemotherapeutic nanomedicines can exploit the neighboring effect to increase tumor penetration. However, the neighboring effect is limited, likely by the consumption of chemotherapeutic agents and resistance of internal hypoxic tumor cells. Here, we first propose and demonstrate that apoptotic bodies (ApoBDs) could carry the remaining drugs to neighboring tumor cells after apoptosis. To enhance the ApoBD-based neighboring effect, we fabricated disulfide-linked prodrug nanoparticles consisting of camptothecin (CPT) and hypoxia-activated prodrug PR104A. CPT kills external normoxic tumor cells to produce ApoBDs, while PR104A remains inactive. The remaining drugs could be effectively delivered into internal tumor cells via ApoBDs. Although CPT exhibits low toxicity to internal hypoxic tumor cells, PR104A could be activated to exert strong cytotoxicity, which further facilitates deep penetration of the remaining drugs. Such a synergic approach could overcome the limitations of the neighboring effect to penetrate deep into solid tumors for whole tumor destruction.

Artificial tumor microenvironment regulated by first hemorrhage for enhanced tumor targeting and then occlusion for synergistic bioactivation of hypoxia-sensitive platesomes

“…The synthesis of PR104A was based on our previous reports 26 , 30 . To synthesize DP, DMG (1 mmol/L), HATU (1.26 mmol/L), NMM (2.47 mmol/L) were stirred in anhydrous acetonitrile at 0 °C for 1 h PR104A (1.5 mmol/L) was subsequently joined in the above reaction system and kept reacting overnight at room temperature.…”

Glutathione Pulse Therapy: Promote Spatiotemporal Delivery of Reduction‐Sensitive Nanoparticles at the “Cellular Level” and Synergize PD‐1 Blockade Therapy

“…The structures of these target prodrugs were confirmed by SolariX Preparation of Prodrug NPs: The LTX-SS-CA NPs were prepared by the one-step nanoprecipitation method. [10,11,31] Prodrugs and DSPE-PEG 2k (weight ratio: 1:0.3) were both added into ethanol (2 mL). After they are totally dissolved, then added dropwise into deionized water (8 mL) with 800 rpm stirring.…”

Advances in the Therapeutic Effects of Apoptotic Bodies on Systemic Diseases

“…Chemotherapeutic nanomedicines can exploit the neighboring effect to increase tumor penetration; however, the neighboring effect is limited due to the consumption of chemotherapeutic drugs and the drug resistance of internal hypoxic tumor cells. ApoBDs were shown to carry the remaining drugs into neighboring tumor cells after apoptosis [ 78 ]. It was reported that camptothecin (CPT) could kill tumor cells with a normal external oxygen content to produce ApoBDs, while the hypoxia-activated prodrug PR104A remained active.…”