Optimizing the stable doxorubicin prodrug nanocomplex for efficient and selective cancer therapy

The rational design of doxorubicin (DOX)-based delivery platforms with efficient and selective features remains a major challenge. The launch of Amphotec®, formed by assembling the positive electrical amphotericin B with negatively electrical sodium cholesterol sulfate (SCS), provides effective reference. Herein, we prepared an acid-sensitive prodrug (DOX-C14) by linking DOX with myristic acid (C14) via the acylhydrazone bond. Then, the positively electrical DOX-C14 was assembled with various negatively electrical cholesterol analogs in different molar ratios to optimize the stable DOX-C14 nanocomplex. Under the combined action of electrostatic and hydrophobic forces, nanocomplexes formed by DOX-C14 with SCS at ratios of 1:2 (DOX-C14-SCS (1:2)) and 1:3 (DOX-C14-SCS (1:3)) exhibited excellent performance. Subsequently, DOX-C14-SCS (1:2) and DOX-C14-SCS (1:3) were modified with DSPE-PEG 2k or CHOL-PEG 2k to further improve their stability and pharmacokinetic behavior. As a result, the obtained PEGylated nanocomplexes could efficiently accumulate in the tumor and then released DOX to exert antitumor effects under the stimulation of acidic environment. Meanwhile, there is no significant toxicity to normal tissues even at very high doses (10 mg/kg equivalent to DOX), demonstrating superior tumor selectivity. Our findings provide novel insights into the rational design of positive electrical drug for efficient and selective cancer therapy.