Co-delivery of autophagy inhibitor and gemcitabine using a pH-activatable core-shell nanobomb inhibits pancreatic cancer progression and metastasis

Abstract

Background: Metastasis is one of the main reasons for the high mortality associated with pancreatic ductal adenocarcinoma (PDAC), and autophagy regulates the metastatic migration of tumor cells, their invasion of tissues, and their formation of focal adhesions. Inhibiting autophagy may suppress tumor growth and metastasis, but the abundant extracellular matrix hinders the deep penetration of therapeutic agents. Methods: To enhance the penetration of drugs that can inhibit metastasis of pancreatic cancer, a pH-responsive drug delivery system was formulated. Gemcitabine (GEM), a first-line chemotherapeutic drug against PDAC, was loaded in 6PA-modified DGL (PDGL) nanoparticles to afford PDGL-GEM. Then PDGL-GEM was co-precipitated with the autophagy inhibitor chloroquine phosphate (CQ) and calcium phosphate to formulate PDGL-GEM@CAP/CQ. The size and morphology of the resulting “nanobomb” PDGL-GEM@CAP/CQ were characterized, and their uptake into cells, cytotoxicity and ability to inhibit autophagy were analyzed at pH 6.5 and 7.4. The anti-tumor and anti-metastasis effects of the nanobomb were explored on mice carrying Pan 02 pancreatic tumor xenografts or orthotopic tumors. Results: The pH-induced dissolution of calcium phosphate facilitated the release of CQ from the nanobomb and deep penetration of PDGL-GEM. The internalization of PDGL-GEM and subsequent intracellular release of GEM inhibited tumor growth, while CQ downregulated autophagy in tumor cells and fibroblasts. In fact, inhibition of xenograft and orthotopic tumor growth was greater with the complete PDGL-GEM@CAP/CQ than with subassemblies lacking GEM or CQ. More importantly, mechanistic studies in vitro and in vivo suggested that the nanobomb inhibits metastasis by downregulating MMP-2 and paxillin, as well as reducing fibrosis. Conclusion: The pH-sensitive PDGL-GEM@CAP/CQ shows potential for inhibiting proliferation and metastasis of pancreatic cancer through an autophagy-dependent pathway.

Autophagy: A Key Player in Pancreatic Cancer Progression and a Potential Drug Target

“…The stroma in some PDAC tumors can account for up to 90% of the tumor mass [ 244 ]. This has led to the development of nanoparticles bound to chemotherapeutics or core capsules that can deliver a nano-bomb of compounds to aid the delivery [ 245 , 246 ]. This protective stroma is fundamental to PDAC survival, aggressive nature and chemotherapeutic resistance.…”

“…PDAC chemotherapy is largely ineffective due to the protective stroma and can be further suppressed if tumor cells are actively opposing apoptosis [ 118 , 295 ]. This interaction could also explain why combination therapy involving autophagy inhibition is highly synergistic [ 179 , 246 , 291 ].…”

pH-responsive hybrid platelet membrane-coated nanobomb with deep tumor penetration ability and enhanced cancer thermal/chemodynamic therapy

“…Therefore, it is necessary to design versatile and biocompatible nanoplatforms for realizing specific delivery and responsible release of ultrasmall nanoparticles. In addition, these nanoplatforms must possess the ability to act as large-sized nanoparticles for high accumulation while behaving as small-sized nanoparticles for deep penetration 11 - 15 . Nanoparticles ranging from 50 to 100 nm in diameter exhibit high tumor accumulation because of quick renal clearance available to the smaller nanoparticles and difficulty in transportation in interendothelial gaps of tumor vasculature in case of the larger ones.…”

“…Nanoparticles ranging from 50 to 100 nm in diameter exhibit high tumor accumulation because of quick renal clearance available to the smaller nanoparticles and difficulty in transportation in interendothelial gaps of tumor vasculature in case of the larger ones. For instance, Shen group reported that the micelles of 100 nm, composed of amphiphilic block copolymers of 7-ethyl-10-hydroxylcamptothecin (SN38) prodrug, could accumulate in tumors best with sizes ranging from 35 and 150 nm 15 . Moreover, in case of nanoparticles smaller than 20 nm, penetration can be deeper than the larger ones owing to the dense extracellular matrix of tumor 11 .…”

Comparison of Anticancer Activities and Biosafety Between Salmonella enterica Serovar Typhimurium ΔppGpp and VNP20009 in a Murine Cancer Model

“…With the development of molecular biology and the deep understanding of the tumor immune microenvironments, BMCT has once again aroused the interest of researchers as a promising approach for cancer therapy. Hypoxia, vascular abnormalities, low pH, and necrotic areas are common features of solid tumors (Guo et al, 2020;Chen et al, 2021b;Kang et al, 2022), and they are the main barriers for traditional therapies. However, they provide favorable conditions for the targeting, colonization, and replication of some obligate or facultative anaerobes.…”