Cyclodextrin Diethyldithiocarbamate Copper II Inclusion Complexes: A Promising Chemotherapeutic Delivery System against Chemoresistant Triple Negative Breast Cancer Cell Lines

Suliman, Ammar Said; Khoder, Mouhamad; Tolaymat, Ibrahim; Webster, Matt; Alany, Raid G.; Wang, Weiguang; Elhissi, Abdelbary; Najlah, Mohammad

doi:10.3390/pharmaceutics13010084

Cited by 22 publications

(24 citation statements)

References 35 publications

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“…This trend is also verified for other compounds under different chromatographic conditions [25]. NDSF = 7 390 − 939 X1 − 2 637 X2 + 951 X22 2 , R 2 = 0.946, R 2 adj = 0.935 (5) NCu(DDC)2 = 10 768 − 985 X1 − 3 484 X2, R 2 = 0.903, R 2 adj = 0.890 (6) Considering the coefficients of Equations ( 5) and ( 6), both factors present a negative impact on this response, although with a higher extent for the % ACN (X2). In addition, the β22 coefficient provides curvature to the DSF model.…”

Section: Theoretical Platessupporting

confidence: 68%

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Expediting Disulfiram Assays through a Systematic Analytical Quality by Design Approach

et al. 2021

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An Analytical Quality by Design (AQbD) approach is presented, aiming at the development and validation of an HPLC method for the quantification of disulfiram and copper diethyldithiocarbamate in lipid nanoparticles. Following the definition of the analytical target profile (ATP), encompassing the critical analytical attributes (CAA), a two-level risk assessment strategy (Ishikawa diagram—failure mode and effect analysis (FMEA)) was employed to identify the critical method parameters (CMPs) with an extensive impact on method performance. The behavior of the CMPs (flow rate and mobile phase composition) was further characterized by experimental design, resorting to a face-centered central composite design (FcCCD). Statistical modeling, response surface analysis, and Monte Carlo simulations led to the definition of the Method Operable Design Region (MODR), associated with a negligible risk of failing the predefined CAA specifications. The optimal method was validated according to international regulatory recommendations. Apart from guaranteeing linearity, accuracy, precision, specificity, robustness, and stability, these conditions were found to be suitable for analysis using a different HPLC column and equipment. In a nutshell, the development and optimization strategies, under the comprehensive framework of AQbD, provided an effective, simple, rapid, reliable, and flexible method for routine analysis of the compounds in research or industrial environments.

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Section: Theoretical Platessupporting

confidence: 68%

“…The reduced aqueous solubility of DSF (0.2 g/L) also impairs its intravenous administration. As for Cu(DDC) 2 , its intrinsic solubility is even lower, estimated as 0.700 µg/L [5]. Their inclusion in nanosystems for cancer drug delivery is thus highly anticipated.…”

Section: Introductionmentioning

confidence: 99%

Expediting Disulfiram Assays through a Systematic Analytical Quality by Design Approach

et al. 2021

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“…In addition to surgery and radiation, chemotherapy which uses broad-spectrum cytotoxic drugs that do not differentiate cancer cells from normal cells, remains as the main arm of cancer treatment, despite its toxicity and significant side effects (Bedard et al, 2020). The discovery of potent metal-based chemotherapeutic drugs such as cisplatin, oxaliplatin and carboplatin paved the way for the development of a new class of inorganic metal-based chemotherapeutic agents (Rottenberg et al, 2021). These metal drugs bind to DNA and block the transcription and replication that initiate the process of apoptosis in cancer cells.…”

Section: Introductionmentioning

confidence: 99%

“…These metal drugs bind to DNA and block the transcription and replication that initiate the process of apoptosis in cancer cells. Platinum drugs are commonly used alone or in combination with other chemotherapeutic agents to treat various malignant diseases such as testicular, lung, breast, ovarian, colon, head and neck cancer (Ndagi et al, 2017;Rottenberg et al, 2021). However, their use is still limited due to innate or acquired resistance in cancer cells and the undesirable side effects associated with their toxicity (Marine et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

Recent Advances in Repurposing Disulfiram and Disulfiram Derivatives as Copper-Dependent Anticancer Agents

Kannappan

Ali

Small

et al. 2021

Front. Mol. Biosci.

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Copper (Cu) plays a pivotal role in cancer progression by acting as a co-factor that regulates the activity of many enzymes and structural proteins in cancer cells. Therefore, Cu-based complexes have been investigated as novel anticancer metallodrugs and are considered as a complementary strategy for currently used platinum agents with undesirable general toxicity. Due to the high failure rate and increased cost of new drugs, there is a global drive towards the repositioning of known drugs for cancer treatment in recent years. Disulfiram (DSF) is a first-line antialcoholism drug used in clinics for more than 65 yr. In combination with Cu, it has shown great potential as an anticancer drug by targeting a wide range of cancers. The reaction between DSF and Cu ions forms a copper diethyldithiocarbamate complex (Cu(DDC)2 also known as CuET) which is the active, potent anticancer ingredient through inhibition of NF-κB and ubiquitin-proteasome system as well as alteration of the intracellular reactive oxygen species (ROS). Importantly, DSF/Cu inhibits several molecular targets related to drug resistance, stemness, angiogenesis and metastasis and is thus considered as a novel strategy for overcoming tumour recurrence and relapse in patients. Despite its excellent anticancer efficacy, DSF has proven unsuccessful in several cancer clinical trials. This is likely due to the poor stability, rapid metabolism and/or short plasma half-life of the currently used oral version of DSF and the inability to form Cu(DDC)2 at relevant concentrations in tumour tissues. Here, we summarize the scientific rationale, molecular targets, and mechanisms of action of DSF/Cu in cancer cells and the outcomes of oral DSF ± Cu in cancer clinical trials. We will focus on the novel insights on harnessing the immune system and hypoxic microenvironment using DSF/Cu complex and discuss the emerging delivery strategies that can overcome the shortcomings of DSF-based anticancer therapies and provide opportunities for translation of DSF/Cu or its Cu(DDC)2 complex into cancer therapeutics.

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“…CDs have a truncated-cone-shaped structure with hydrophilic surfaces and hydrophobic cavities. This unique structure allows them to entrap poorly soluble drug moieties, such as natural antioxidants and anticancer drugs, in their hydrophobic cavities to form inclusion complexes [59]. Several factors contribute to an effective formation of an inclusion complex.…”

Section: Cyclodextrins (Cds) 41 General Conceptmentioning

confidence: 99%

Sunscreens Containing Cyclodextrin Inclusion Complexes for Enhanced Efficiency: A Strategy for Skin Cancer Prevention

et al. 2021

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Unprotected exposure of skin to solar ultraviolet radiation (UVR) may damage the DNA of skin cells and can lead to skin cancer. Sunscreens are topical formulations used to protect skin against UVR. The active ingredients of sunscreens are UV filters that absorb, scatter, and/or reflect UVR. Preventing the formation of free radicals and repairing DNA damages, natural antioxidants are also added to sunscreens as a second fold of protection against UVR. Antioxidants can help stabilise these formulations during the manufacturing process and upon application on skin. However, UV filters and antioxidants are both susceptible to degradation upon exposure to sunlight and oxygen. Additionally, due to their poor water solubility, natural antioxidants are challenging to formulate and exhibit limited penetration and bioavailability in the site of action (i.e., deeper skin layers). Cyclodextrins (CDs) are cyclic oligosaccharides that are capable of forming inclusion complexes with poorly soluble drugs, such as antioxidants. In this review, we discuss the use of CDs inclusion complexes to enhance the aqueous solubility of antioxidants and chemical UV filters and provide a protective shield against degradative factors. The role of CDs in providing a controlled drug release profile from sunscreens is also discussed. Finally, incorporating CDs inclusion complexes into sunscreens has the potential to increase their efficiency and hence improve their skin cancer prevention.

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Cyclodextrin Diethyldithiocarbamate Copper II Inclusion Complexes: A Promising Chemotherapeutic Delivery System against Chemoresistant Triple Negative Breast Cancer Cell Lines

Cited by 22 publications

References 35 publications

Expediting Disulfiram Assays through a Systematic Analytical Quality by Design Approach

Expediting Disulfiram Assays through a Systematic Analytical Quality by Design Approach

Recent Advances in Repurposing Disulfiram and Disulfiram Derivatives as Copper-Dependent Anticancer Agents

Sunscreens Containing Cyclodextrin Inclusion Complexes for Enhanced Efficiency: A Strategy for Skin Cancer Prevention

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