Redirecting Transport of Nanoparticle Albumin-Bound Paclitaxel to Macrophages Enhances Therapeutic Efficacy against Liver Metastases

Abstract

Current treatments for liver metastases arising from primary breast and lung cancers are minimally effective. One reason for this unfavorable outcome is that liver metastases are poorly vascularized, limiting the ability to deliver therapeutics from the systemic circulation to lesions. Seeking to enhance transport of agents into the tumor microenvironment, we designed a system in which nanoparticle albumin-bound paclitaxel (nAb-PTX) is loaded into a nanoporous solid multistage nanovector (MSV) to enable the passage of the drug through the tumor vessel wall and enhance its interaction with liver macrophages. MSV enablement increased nAb-PTX efficacy and survival in mouse models of breast and lung liver metastasis. MSV-nAb-PTX also augmented the accumulation of PTX and MSV in the liver, specifically in macrophages, whereas PTX levels in the blood were unchanged after administering MSV-nAb-PTX or nAb-PTX. In vitro studies demonstrated that macrophages treated with MSV-nAb-PTX remained viable and were able to internalize, retain, and release significantly higher quantities of PTX compared to treatment with nAb-PTX. The cytotoxic potency of the released PTX was also confirmed in tumor cells cultured with the supernatants of macrophage treated with MSV-nAB-PTX. Collectively, our findings showed how redirecting nAb-PTX to liver macrophages within the tumor microenvironment can elicit a greater therapeutic response in patients with metastatic liver cancer, without increasing systemic side-effects.

Enhanced performance of macrophage-encapsulated nanoparticle albumin-bound-paclitaxel in hypo-perfused cancer lesions

“…In contrast, the MSV-nAb-PTX therapy is projected to achieve a 71% radius decline by treatment completion. The order of magnitude of the endpoints from the in silico results (Fig 6c) are in agreement with a comparable in vivo study (Fig 6d) we have recently reported 19 . By the end of 9 days, the tumor diameter after in silico treatment with nAb-PTX and MSV-nAb-PTX was 2.9- and 14.1-fold of the untreated control, respectively (Fig 6c), while the in vivo results showed regression of 3.7- and 17.1-fold, respectively (Fig 6d).…”

“…Previously 19 , we designed a multistage system in which nanoparticle albumin bound paclitaxel (nAb-PTX) was packaged into solid particles to increase interaction with macrophages. nAb-PTX is clinically employed for therapy of advanced breast tumors 20, 21 , although its efficacy with liver metastasis is usually lacking and can cause hepatic toxicity 22 .…”

“…To enhance nAb-PTX efficacy, we shifted its transport from endothelial cells towards liver macrophages by encapsulating nAb-PTX in a biocompatible and biodegradable multi-stage nanovector (MSV) system 24, 25 . The newly designed MSV-nAb-PTX was observed to efficiently increase survival in a mouse model of liver metastasis 19 . Further in vivo studies showed a significantly increased therapeutic response of liver tumors treated with MSV-nAb-PTX compared to nAb-PTX 19 .…”

“…The newly designed MSV-nAb-PTX was observed to efficiently increase survival in a mouse model of liver metastasis 19 . Further in vivo studies showed a significantly increased therapeutic response of liver tumors treated with MSV-nAb-PTX compared to nAb-PTX 19 . In spite of such significant positive results, the in vivo studies did not allow for the drug transport evaluation at the cellular level, required to model the therapeutic response in humans.…”

Polyethylenimine-functionalized silver nanoparticle-based co-delivery of paclitaxel to induce HepG2 cell apoptosis

“…Paclitaxel (PTX), a chemotherapeutic agent, is widely used against several types of solid tumors besides breast, ovarian, lung, colon, head, neck, and liver cancers. [21][22][23][24][25][26][27] PTX disrupts the tubulin-microtubule equilibrium, which is different from conventional anticancer drugs affecting nucleic acid synthesis to induce cancer cell death. 28,29 It is considered as an appropriate candidate for chemotherapy because PTX at low concentrations can exert antiangiogenic activity.…”