Helix Self-Assembly Behavior of Amino Acid-Modified Camptothecin Prodrugs and Its Antitumor Effect

Abstract

For effective antitumor treatment, it is important to increase the water solubility of hydrophobic antitumor drugs and improve their cell absorption efficiency and nuclear transmission capacity. Here, we use endogenous hydrophilic arginine to modify camptothecin (CPT) to increase its water solubility. Surprisingly, the modified CPT can self-assemble into helical nanofibers through intermolecular π–π stacking and hydrophilic–hydrophobic interactions. Prodrug-based nanofibers were better endocytosed into the nucleus than their nonassembled CPT. Moreover, in vivo, such nanofibers had a longer blood circulation time and a better ability to accumulate in the tumor site. Further, we found that the cationic nanofibers can be combined with the anionic cisplatin–polyglutamic acid through electrostatic interaction to achieve a combined antitumor effect. This provides a new idea for achieving more effective cancer chemotherapy effects.

Small‐Molecule Prodrug Nanoassemblies: An Emerging Nanoplatform for Anticancer Drug Delivery

“…[ 59 ] The camptothecin–arginine (CPT–AR) prodrug was synthesized to investigate the self‐assembly mechanisms of the nanofibers. [ 64 ] First, the strong π–π stacking interactions between the quinoline rings of CPT drove the CPT–AR molecules to self‐aggregate into nanoribbons via an edge‐to‐edge pattern. Afterward, the nanoribbons curled into helical nanofibers, and the hydrogen bond between CPT and guanidine might participate in the formation of the nanostructure.…”

“…Reproduced with permission. [ 64 ] Copyright 2020, American Chemical Society. D 1 ) Schematic illustration of the Ir–Qu heterodimer nanoassemblies.…”

“…In a work, the cationic CPT–CR fibrous nanoassemblies (CRA) were complexed with the anionic cisplatin‐polyglutamic acid (CisPt‐PPG) through electrostatic interactions (Figure 15C). [ 64 ] The ratio of CPT and cisplatin could be freely adjusted. The CRA/CisPt‐PPG co‐delivery system at a ratio of 1:1 finally exhibited the strongest anti‐tumor effect and the lowest systemic toxicity.…”

Self-assembly of amino acids toward functional biomaterials

“…However, camptothecin has some major limitations in therapeutic applications, such as poor water solubility and rapid lactone ring hydrolysis at physiological pH values, which leads to inactive carboxylate forms [ 91 – 92 ]. Guo et al [ 93 ] obtained water-soluble spiral nanofibers by coupling hydrophilic arginine and camptothecin. Self-assembly behavior is achieved by intermolecular π–π stacking and hydrophilic–hydrophobic interactions.…”

Carrier-free nanodrugs for safe and effective cancer treatment

“…CPT is mainly used for the treatments of lung, breast and brain cancers and has a planar pentacyclic ring structure which causes cylindric shaped aggregations in water. Biological environment causes the degradation of CPT in only thirty minutes by hydrolysis of its lactone rings and CPT has very poor water solubility (2-3 μg/mL) [13,14]. Therefore, derivatives of CPT have been developed in order to increase its solubility and stability in physiological conditions.…”