Versatile Prodrug Nanoparticles for Acid‐Triggered Precise Imaging and Organelle‐Specific Combination Cancer Therapy

Abstract

Integration of chemotherapy with photodynamic therapy (PDT) has been emerging as a novel strategy for treatment of triple negative breast cancer (TNBC). However, the clinical translation of this approach is hindered by the unwanted dark toxicity due to the “always‐on” model and low tumor specificity of currently approved photosensitizer (PS). Here, the design of a multifunctional prodrug nanoparticle (NP) is described for precise imaging and organelle‐specific combination cancer therapy. The prodrug NP is composed of a newly synthesized oxaliplatin prodrug, hexadecyl‐oxaliplatin‐trimethyleneamine (HOT), an acid‐activatable PS, derivative of Chlorin e6 (AC), and functionalized with a targeting ligand iRGD for tumor homing and penetration. HOT displays much higher antitumor efficiency than oxaliplatin by simultaneously inducing mitochondria depolarizing and DNA cross‐linking. AC is specifically activated in the orthotopic or metastatic TNBC tumor for fluorescence imaging and PDT, while it remains inert in blood circulation to minimize the dark toxicity. Under the guide of acid‐activatable fluorescence imaging, PDT and chemotherapy can be synergistically performed for highly efficient regression of TNBC. Taken together, this versatile prodrug nanoplatform could achieve tumor‐specific imaging and organelle‐specific combination therapy, which can provide an alternative option for cancer theranostic.

The role of reactive oxygen species in tumor treatment

“…19 With the aim to overcome the PS toxicity caused by non-specic targeting, B. Feng et al synthesized a multifunctional prodrug nanosystem loaded with hexadecyl-oxaliplatin-trimethyleneamine (prodrug, HOT) and derivative of Chlorin e6 (acid-activatable PS, AC). 20 Aer the nanosystem was modied with iRGD, a targeting ligand, it could function for tumor homing and penetration. AC will minimize the toxicity during the blood circulation, while its specic acid-response in orthotopic or metastatic tumor could enhance the uorescence imaging and PDT.…”

Theranostic Prodrug Vesicles for Reactive Oxygen Species‐Triggered Ultrafast Drug Release and Local‐Regional Therapy of Metastatic Triple‐Negative Breast Cancer

“…Meanwhile, several independent groups including ourselves have demonstrated that NIR laser‐conducted photodynamic therapy (PDT) prompted up the drug release in the tumor tissue or inside the cancer cells by inducing reactive oxygen species (ROS) generation to degrade the ECM or endocytic vesicles . Moreover, PDT was utilized to activate the therapeutic payloads and selectively destroy the tumor cells without affecting the nearby normal tissues . Despite being promising, the design of versatile nanovectors to address the sequential barriers for highly efficient cancer therapy remains a formidable challenge.…”

Programmed Multiresponsive Vesicles for Enhanced Tumor Penetration and Combination Therapy of Triple‐Negative Breast Cancer

“…Oxaliplatin (OXA) and DOX are both the first‐line chemotherapeutics clinically used for the treatment of various carcinomas including colonic and breast cancers . To demonstrate the potential of ELTSL for combination chemotherapy of TNBC, we first synthesized a lipophilic OXA prodrug of hexadecyl‐oxaliplatin carboxylic acid (HOC) according to a procedure we reported previously (Figures S10 and S11, Supporting Information) . HOC is a Pt (IV) prodrug, which is inert in the blood circulation and is activated in the tumor cells by reducing HOC (IV) to OXA (II) with the endogenous glutathione (GSH).…”