TPGS–Galactose-Modified Polydopamine Co-delivery Nanoparticles of Nitric Oxide Donor and Doxorubicin for Targeted Chemo–Photothermal Therapy against Drug-Resistant Hepatocellular Carcinoma

Abstract

The lack of cancer cell specificity and the occurrence of multidrug resistance (MDR) are two major obstacles in the treatment of hepatocellular carcinoma (HCC). To tackle these challenges, a novel nanoparticle (NP)-based drug delivery system (DDS) with a core/shell structure consisted of d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS)–galactose (Gal)/polydopamine (PDA) is fabricated. The NP is loaded with doxorubicin (DOX) and a nitric oxide (NO) donor N,N′-di-sec-butyl-N,N′-dinitroso-1,4-phenylenediamine (BNN) sensitive to heat to afford NO-DOX@PDA-TPGS-Gal. The unique binding of Gal to asialoglycoprotein receptor (ASGPR) and the pH-sensitive degradation of NP ensure the targeted transportation of NP into liver cells and the release of DOX in HCC cells. The near-infrared (NIR) light further facilitates DOX release and initiates NO generation from BNN due to the photothermal property of PDA. In addition to the cytotoxicity contributed by DOX, NO, and heat, TPGS and NO act as MDR reversal agents to inhibit P-glycoprotein (P-gp)-related efflux of DOX by HepG2/ADR cells. The combined chemo–photothermal therapy (chemo-PTT) by NO-DOX@PDA-TPGS-Gal thus shows potent anti-cancer activity against drug-resistant HCC cells in vitro and in vivo and significantly prolongs the life span of drug-resistant tumor-bearing mice. The present work provides a useful strategy for highly targeted and MDR reversal treatment of HCC.

Orally Administered Halofuginone-Loaded TPGS Polymeric Micelles Against Triple-Negative Breast Cancer: Enhanced Absorption and Efficacy with Reduced Toxicity and Metastasis

“… 46 It is well known that TPGS can suppress the efflux of P-gp by inhibiting the ATPase activity. 47 In the present study, we found that the P app value (AP→BL) of HTPM was significantly increased, while their P app value (BL→AP) was markedly decreased compared with that of HF ( Figure 4A and B ), and the resultant ER of HTPM was reduced to 1.21, demonstrating that polymeric micelles self-assembled by TPGS can inhibit the efflux of P-gp against HF in Caco-2 cell monolayers. Incubation with verapamil further influenced the bidirectional P app value and ER of HTPM, but there was no significant change compared with that of HTPM alone.…”

Polyphenol‐Based Nanosystems for Next‐Generation Cancer Therapy: Multifunctionality, Design, and Challenges

“…For example, Du et al used the photothermal action of polydopamine to pyrolyze the NO donor BNN, and the generated NO could re-sensitize drugresistant cells to chemotherapy. [59] Based on the above evidence, polyphenols, which enhance drug retention and sensitize cancer cells to therapeutic agents, have the potential to be promising biomaterials against tumor multidrug resistance.…”

Review of Functionalized Nanomaterials for Photothermal Therapy of Cancers

“…Polydopamine (PDA) is another polymer NIR-absorbing material that has attracted extensive attention. As an important component of melanin, which is widely distributed in the human body, PDA has obvious advantages in biosafety. , Many studies have shown that PDA may not interfere with the activity and proliferation of a variety of mammalian cells and that it may not cause remarkable cytotoxicity even at a very high dose. More importantly, PDA has been proven to be completely degradable in vivo and has higher safety than other conjugated polymers. − In terms of its optical properties, PDA has light absorption properties similar to those of melanin.…”