Bortezomib‐Encapsulated Dual Responsive Copolymeric Nanoparticles for Gallbladder Cancer Targeted Therapy

Abstract

Gallbladder cancer (GBC) is a rare but the most malignant type of biliary tract tumor. It is usually diagnosed at an advanced stage and conventional treatments are unsatisfactory. As a proteasome inhibitor, bortezomib (BTZ) exhibits excellent antitumor ability in GBC. However, the long‐term treatment efficacy is limited by its resistance, poor stability, and high toxicity. Herein, BTZ‐encapsulated pH‐responsive copolymeric nanoparticles with estrone (ES‐NP(BTZ; Ce6)) for GBC‐specific targeted therapy is reported. Due to the high estrogen receptor expression in GBC, ES‐NP(BTZ; Ce6) can rapidly enter the cells and accumulate near the nucleus via ES‐mediated endocytosis. Under acidic tumor microenvironment (TME) and 808 nm laser irradiation, BTZ is released and ROS is generated by Ce6 to destroy the “bounce‐back” response pathway proteins, such as DDI2 and p97, which can effectively inhibit proteasomes and increase apoptosis. Compared to the traditional treatment using BTZ monotherapy, ES‐NP(BTZ; Ce6) can significantly impede disease progression at lower BTZ concentrations and improve its resistance. Moreover, ES‐NP(BTZ; Ce6) demonstrates similar antitumor abilities in patient‐derived xenograft animal models and five other types of solid tumor cells, revealing its potential as a broad‐spectrum antitumor formulation.

Advantages of Nanomedicine in Cancer Therapy: A Review

“…51 An exemplary case involves the work of Chen et al, who pioneered bortezomib-loaded bioresponsive nanoparticles incorporating estrone for targeted therapy in gallbladder cancer (GBC). 52 Leveraging the high expression of estrogen receptors in GBC, these nanoparticles rapidly entered cells and accumulated near the nucleus through ES-mediated endocytosis. Similarly, in a triple-negative breast cancer model, a supramolecular self-delivery nanomedicine was tailored to achieve in situ transformation, effectively inhibiting tumor growth and metastasis.…”

“…An exemplary case involves the work of Chen et al, who pioneered bortezomib-loaded bioresponsive nanoparticles incorporating estrone for targeted therapy in gallbladder cancer (GBC) . Leveraging the high expression of estrogen receptors in GBC, these nanoparticles rapidly entered cells and accumulated near the nucleus through ES-mediated endocytosis.…”

Nucleus-Targeting Nanoplatform Based on Dendritic Peptide for Precise Photothermal Therapy

“…Among them, photothermal therapy (PTT), as a new antitumor method, has the advantages of strong control ability, deep tissue penetration, high treatment efficiency, and weak side effects [ 6 , 7 ]. When PTT directly anchors to the nucleus, it can damage DNA by accurately nucleus-burning, thereby destroying the function and behavior of cells and achieving efficient cell killing ability [ 8 , 9 ]. More importantly, the precise destruction of the nucleus can effectively cutoff the triggering of inhibition mechanisms to photothermal effect, such as the up-regulation of intracellular heat shock protein, so as to ensure the efficient killing ability of tumor cells and inhibit the occurrence of metastasis [ 10 , 11 ].…”

Bortezomib-loaded mixed micelles realize a “three-in-one” effect for enhanced breast cancer treatment

“…However, BTZ has poor stability in vivo, because the boric acid group is prone to chelation and makes the drug invalid. 38,39 Besides, BTZ cannot be administered orally and requires frequent administration to maintain the in vivo inhibiting ability on proteasome; moreover, most solid tumors exhibit intrinsic resistance to BTZ, making it less effective in solid tumors. 40,41 Additionally, the unspecific systemic distribution as a free drug makes BTZ unable to efficiently accumulate at the tumor site as well as causing serious adverse drug reactions.…”

“…In the past few decades, nano-scaled drug delivery systems have attracted great attention owing to the well-controlled drug release, improved tumor accumulation, enhanced antitumor efficacy, reduced side effects, etc. 38,[45][46][47][48] Among them, lipid/glycocholic acid mixed micelles (LGs) are widely studied and applied with desired biocompatibility and biodegradability. 49 LGs hold promising clinical translation potential due to their simple compositions and controllable preparation process.…”