A pH-responsive complex based on supramolecular organic framework for drug-resistant breast cancer therapy

Abstract

Chemotherapy is one of the main ways to treat breast cancer clinically. However, the multidrug resistance to anti-tumor drugs limits their clinical use. To overcome these drawbacks, development of drug delivery systems (DDSs) has attracted more and more attention in cancer therapy. At present, the preparation and purification process are complicated for many reported DDSs, while clinic calls for new DDSs that are more convenient for preparation. Here, a new pH-responsive supramolecular organic framework drug delivery complex loading doxorubicin (DOX) is fabricated. Anti-tumor activity of the system in vitro was investigated by cell cytotoxicity, uptake assay, and cell apoptosis analysis. The anti-tumor activity in vivo was investigated by inspecting nude mice body weight, tumor volume, and weight, also a preliminary mechanism probe was conducted by HE and TUNEL staining. The DOX@SOF displayed high stability, good biocompatibility, and pH regulated drug release. At acid condition, the hydrazone bonds would be broken, which result in the dissociation of SOF, and then the drugs would be released from the system. Furthermore, DOX@SOF enhanced cellular internalization. Both in vitro and in vivo experiments reflected that DOX@SOF could enhance the anti-tumor activity of DOX for the MCF-7/ADR tumor cells and tumors. This study provides a highly efficient strategy to prepare stimulus-responsive supramolecular drug delivery complex for treatment of drug-resistant cancer, the results presented inspiring scientific interests in exploring new drug delivery strategy and reversing multi-drug resistance for clinical chemotherapy.

Supramolecular Organic Frameworks: Exploring Water-Soluble, Regular Nanopores for Biomedical Applications

“…We thus prepared hydrazone derivative T2 (Chart 1) to test this possibility because the acid-responsive hydrolysis of hydrazone has been widely used for the design of drug delivery systems and prodrugs. 49 Its 1:2 mixture with CB [8] led to the formation of dSOF2, 32 which has an aperture of 2.7 nm. Both in vitro and in vivo experiments showed that dSOF2 could also include doxorubicin and enhance its activity against MCF-7/ADR cells and tumors through intracellular delivery.…”

“…dSOF1a – h were prepared in boiling water at the highest concentration of the tetrahedral components ,,− ,− but could maintain their nanoscale sizes at the low concentration of 50 μM at room temperature, indicating that the peripheral substituents of the tetrahedral components did not affect the stability of the frameworks. Therefore, they could not only function as antidotes to neutralize the anticoagulation activity of residual heparins and alleviate the posttreatment phototoxicity of residual PDAs but also work well as nonequilibrium carriers, conducting in situ loading and the intracellular delivery of antitumor drugs and PDAs, ,,,, which has been ascribed to the so-called enhanced permeability and retention (EPR) effect . Apart from inclusion-based biomedical applications, dSOFs can also be conjugated with antitumor agents, forming new supramolecular prodrugs to attain enhanced efficacy .…”

Conjugating aldoxorubicin to supramolecular organic frameworks: polymeric prodrugs with enhanced therapeutic efficacy and safety

“…31,32 Previously we found that SOFs can in situ load anticancer agents and overcome the multidrug resistance of tumour cells to realize intracellular drug delivery and efficacy enhancement through the EPR effect. 32–35 Because the tetrahedral components can be readily functionalized at the ends of the appended aromatic units, 36 we conjectured that SOFs might be developed as albumin surrogates to conjugate AlDox or other small-molecule anticancer agents to attain increased efficacy through efficient conjugation, intracellular delivery and stimuli-responsive release. Here we describe the preparation of two SOF-based prodrugs by attaching AlDox to the interior of their regular pores through the thiol–maleimide conjugation approach.…”

Flexible organic frameworks sequester neuromuscular blocking agents in vitro and reverse neuromuscular block in vivo

“…22,23 Herein, we explore the sequestration of NMBAs by framework materials. Metal-organic frameworks (MOFs), [24][25][26] covalent-organic frameworks (COFs) 27,28 and supramolecularorganic frameworks (SOFs) [29][30][31] are important framework materials. To sequester NMBAs, we use a new type of frameworks, flexible organic frameworks (FOFs), which are biocompatible, stable and capable of encapsulating pharmaceutical or biological guests [32][33][34] .…”