Triple-Layered pH-Responsive Micelleplexes Loaded with siRNA and Cisplatin Prodrug for NF-Kappa B Targeted Treatment of Metastatic Breast Cancer

Abstract

The combination of chemotherapy and RNA interference is a promising approach for efficient cancer therapy. However, the success of such a strategy is hampered by the lack of suitable vectors to coordinate small interfering RNA (siRNA) and chemotherapeutic drug into one single platform. We herein report a novel triple-layered pH-responsive micelleplex loading siRNA and alkylated cisplatin prodrug for NF-Kappa B targeted treatment of metastatic breast cancer. The micelles were self-assembled from poly(ethylene glycol)-block-poly(aminolated glycidyl methacrylate)-block-poly(2-(diisopropyl amino) ethyl methacrylate) (PEG-b-PAGA-b-PDPA) triblock copolymers. At pH 7.4, the cisplatin prodrug was encapsulated in the hydrophobic PDPA core and siRNA was loaded on the positively charged PAGA interlayer to form the micelleplexes. The PEG corona can prevent protein absorption during blood circulation, minimize non-specific interaction with the reticuloendothelial system, and prolong the systemic circulation of the micelleplexes. The positively charged PAGA interlayer can facilitate deep tumor penetration of the micelleplexes, which, upon cellular uptake, are dissociated in the early endosomes to release anticancer drug payload due to protonation of the PDPA core. Using a 4T1 breast cancer model, we demonstrate that this novel micelleplex co-loaded with cisplatin prodrug and siRNA-p65 is able to simultaneously inhibit tumor growth and suppress distant metastasis of the cancer cells by downregulating NF-kappa B expression. The results reported in this study suggest that siRNA and anticancer drug co-delivery using pH-responsive micelleplexes is a promising strategy for efficient treatment of metastatic cancer.

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

“…The 4T1 tumor model we used in this study is a highly aggressive TNBC tumor model, which is potent for distant lung metastasis . Figure A,B showed chemotherapy with Dox marginally inhibited tumor metastasis to the lung.…”

“…Monotherapy or neoadjuvant chemotherapy using cytotoxic drugs is currently the standard‐of‐care for clinical treatment of advanced or metastatic TNBC . Unfortunately, systemic chemotherapy suffers from the severe side effects and the occurrence of acquired drug resistance due to nonspecific drug distribution to the normal tissues while insufficient drug delivery to the tumor in vivo . Recent study also revealed that systemic chemotherapy suppressed the immune activity by damaging the bone marrow and subsequently reduced the number of resident immune T cells, which impaired the therapeutic outcome of systemic chemotherapy …”

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

“…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). Such a prodrug strategy has been employed to improve the therapeutic outcomes of platinum drugs (e.g., OXA and cisplatin) while to suppress their side effect . The combination of DOX and HOC displayed a therapeutic combination index (CI) < 1.0 in 4T1 cells calculated according to a reported approach, indicating DOX potentially sensitized TNBC cells to HOC treatment (Table S1 and Figure S12, Supporting Information).…”

RNA Interference and Current Clinical Applications: Review

“…33 siRNA temelli tedavideki en büyük zorluklardan birisi sistemik taşınımla hedefe ulaşım olduğundan, son yıllarda siRNAların kimyasal modifikasyonu, biyoaktif moleküllere siRNA konjugasyonu ve taşınım formulasyonları ile ilgili çalışmalar yoğun şe-kilde devam etmektedir. [40][41][42][43][44][45] RNAi temelli tedavi yöntemlerinde immün cevap ve toksisite de bir başka problemdir. RNAi mekanizması, vücudu istenmeyen patojenlerden korumak için yer alan doğuştan bir immün cevap sistemidir.…”