Guided molecular missiles for tumor-targeting chemotherapy--case studies using the second-generation taxoids as warheads

A long-standing problem in cancer chemotherapy is the lack of tumor-specific treatments. Traditional chemotherapy relies on the premise that rapidly proliferating cancer cells are more likely to be killed by a cytotoxic agent. In reality, however, cytotoxic agents have very little or no specificity, which leads to systemic toxicity, causing undesirable severe side effects. Therefore, the development of innovative and efficacious tumor-specific drug delivery protocols or systems is urgently needed. A rapidly growing tumor requires various nutrients and vitamins. Thus, tumor cells overexpress many tumor-specific receptors, which can be used as targets to deliver cytotoxic agents into tumors. This Account presents our research program on the discovery and development of novel and efficient drug delivery systems, possessing tumor-targeting ability and efficacy against various cancer types, especially multidrug-resistant tumors. In general, a tumor-targeting drug delivery system consists of a tumor recognition moiety and a cytotoxic warhead connected directly or through a suitable linker to form a conjugate. The conjugate, which can be regarded as a "guided molecular missile", should be systemically nontoxic, that is, the linker must be stable in blood circulation, but upon internalization into the cancer cell, the conjugate should be readily cleaved to regenerate the active cytotoxic warhead. These novel "guided molecular missiles" are conjugates of the highly potent second-generation taxoid anticancer agents with tumor-targeting molecules through mechanism-based cleavable linkers. These conjugates are specifically delivered to tumors and internalized into tumor cells, and the potent taxoid anticancer agents are released from the linker into the cytoplasm. We have successfully used omega-3 polyunsaturated fatty acids, in particular DHA, and monoclonal antibodies (for EGFR) as tumor-targeting molecules for the conjugates, which exhibited remarkable efficacy against human tumor xenografts in animal models. We have developed self-immolative disulfide linkers wherein the glutathione-triggered cascade drug release takes place to generate the original anticancer agent. The use of disulfide linkers is attractive beacuse it takes into account the fact that the concentration of glutathione is much higher (>1000 times) in tumor cells than in blood plasma. In order to monitor and elucidate the mechanism of tumor-targeting, internalization, and drug release, several fluorescent and fluorogenic probes using biotin as the tumor-targeting module were developed and used. Then, the progressive occurrence of the designed receptor-mediated endocytosis, drug release, and drug binding to the target protein (microtubules) has been successfully observed and confirmed by means of confocal fluorescence microscopy. These "guided molecular missiles" provide bright prospects for the development of highly efficacious new generation drugs for cancer chemotherapy.     

纳米材料介导的siRNA和抗癌药物递送系统的研究进展

RNA干扰(RNAi)正逐步成为癌症治疗中强而有力的技术手段。siRNA可被设计用于特异沉默那些参与耐药及化疗无效基因的表达,是一种重要的RNAi的工具。目前,可以通过si RNA和其他组合疗法的协同效应来提高抗肿瘤药物的治疗效果。然而,共同递送这些多样的抗癌药物需要设计相应的纳米载体。将重点介绍基于脂质体、聚合物和无机纳米载药体系的si RNA和抗癌药物共同递送系统,并讨论基于纳米载体递送系统下的si RNA及抗癌药物的联用情况。     

The application of carbon nanotubes in target drug delivery systems for cancer therapies

Among all cancer treatment options, chemotherapy continues to play a major role in killing free cancer cells and removing undetectable tumor micro-focuses. Although chemotherapies are successful in some cases, systemic toxicity may develop at the same time due to lack of selectivity of the drugs for cancer tissues and cells, which often leads to the failure of chemotherapies. Obviously, the therapeutic effects will be revolutionarily improved if human can deliver the anticancer drugs with high selectivity to cancer cells or cancer tissues. This selective delivery of the drugs has been called target treatment. To realize target treatment, the first step of the strategies is to build up effective target drug delivery systems. Generally speaking, such a system is often made up of the carriers and drugs, of which the carriers play the roles of target delivery. An ideal carrier for target drug delivery systems should have three pre-requisites for their functions: (1) they themselves have target effects; (2) they have sufficiently strong adsorptive effects for anticancer drugs to ensure they can transport the drugs to the effect-relevant sites; and (3) they can release the drugs from them in the effect-relevant sites, and only in this way can the treatment effects develop. The transporting capabilities of carbon nanotubes combined with appropriate surface modifications and their unique physicochemical properties show great promise to meet the three pre-requisites. Here, we review the progress in the study on the application of carbon nanotubes as target carriers in drug delivery systems for cancer therapies.     

Double Repositioning: Veterinary Antiparasitic to Human Anticancer

Drug repositioning, the approach of discovering different uses for existing drugs, has gained enormous popularity in recent years in the anticancer drug discovery field due to the increasing demand for anticancer drugs. Additionally, the repurposing of veterinary antiparasitic drugs for the treatment of cancer is gaining traction, as supported by existing literature. A prominent example is the proposal to implement the use of veterinary antiparasitics such as benzimidazole carbamates and halogenated salicylanilides as novel anticancer drugs. These agents have revealed pronounced anti-tumor activities and gained special attention for “double repositioning”, as they are repurposed for different species and diseases simultaneously, acting via different mechanisms depending on their target. As anticancer agents, these compounds employ several mechanisms, including the inhibition of oncogenic signal transduction pathways of mitochondrial respiration and the inhibition of cellular stress responses. In this review, we summarize and provide valuable information about the experimental, preclinical, and clinical trials of veterinary antiparasitic drugs available for the treatment of various cancers in humans. This review suggests the possibility of new treatment options that could improve the quality of life and outcomes for cancer patients in comparison to the currently used treatments.     

Differentiation of Cancer Stem Cells by Using Synthetic Small Molecules: Toward New Therapeutic Strategies against Therapy Resistance

Despite the existing arsenal of anti-cancer drugs, 10 million people die each year worldwide due to cancers; this highlights the need to discover new therapies based on innovative modes of action against these pathologies. Current chemotherapies are based on the use of cytotoxic agents, targeted drugs, monoclonal antibodies or immunotherapies that are able to reduce or stop the proliferation of cancer cells. However, tumor eradication is often hampered by the presence of resistant cells called cancer stem-like cells or cancer stem cells (CSCs). Several strategies have been proposed to specifically target CSCs such as the use of CSC-specific antibodies, small molecules able to target CSC signaling pathways or drugs able to induce CSC differentiation rendering them sensitive to classical chemotherapy. These latter compounds are the focus of the present review, which aims to report recent advances in anticancer-differentiation strategies. This therapeutic approach was shown to be particularly promising for eradicating tumors in which CSCs are the main reason for therapeutic failure. This general view of the chemistry and mechanism of action of compounds inducing the differentiation of CSCs could be particularly useful for a broad range of researchers working in the field of anticancer therapies as the combination of compounds that induce differentiation with classical chemotherapy could represent a successful approach for future therapeutic applications.     

Natural Phytochemicals Derived from Gymnosperms in the Prevention and Treatment of Cancers

The incidence of various types of cancer is increasing globally. To reduce the critical side effects of cancer chemotherapy, naturally derived compounds have been considered for cancer treatment. Gymnosperms are a group of plants found worldwide that have traditionally been used for therapeutic applications. Paclitaxel is a commercially available anticancer drug derived from gymnosperms. Other natural compounds with anticancer activities, such as pinostrobin and pinocembrin, are extracted from pine heartwood, and pycnogenol and enzogenol from pine bark. Gymnosperms have great potential for further study for the discovery of new anticancer compounds. This review aims to provide a rational understanding and the latest developments in potential anticancer compounds derived from gymnosperms.     

Polymer-functionalized carbon nanotubes in cancer therapy: a review

The increasing importance of nanotechnology in the field of biomedical applications has encouraged the development of new nanomaterials endowed with multiple functions. Novel nanoscale drug delivery systems with diagnostic, imaging and therapeutic properties hold many promises for the treatment of different types of diseases, including cancer, infection and neurodegenerative syndromes. Carbon nanotubes (CNTs) are both low-dimensional sp² carbon nanomaterials exhibiting many unique physical and chemical properties that are interesting in a wide range of areas including nanomedicine. Since 2004, CNTs have been extensively explored as drug delivery carriers for the intracellular transport of chemotherapy drugs, proteins and genes. In vivo cancer treatment with CNTs has been demonstrated in animal experiments by several different groups. Herein, the recent works on anticancer drug delivery systems based on carbon nanotubes are reviewed and some of more specific and important novel drug delivery devices are discussed in detail. This paper focuses on modifications of CNTs by polymers through covalent and non-covalent attachments: two different methods as critical steps in preparation of anticancer drug delivery systems from CNTs. In this respect the in vivo and in vitro behaviors and toxicity of the CNTs modified by polymers are summarized as well. Well-functionalized CNTs did not show any significant toxicity after injection into mice. Moreover, administration and excretion of CNT-based nanocarriers are discussed. It was concluded that future development of CNT-based nanocarriers may bring novel opportunities to cancer diagnosis and therapy.     

Rhenium-Based Complexes and in Vivo Testing: A Brief History

The success of metal-based anticancer therapeutics in the treatment of cancer is best exemplified by cisplatin. Currently used in 32/78 cancer regimens, metal-based drugs have a clear role in cancer therapy. Despite this, metal-based anticancer therapeutics are not without drawbacks, with issues such as toxic side effects and the development of resistance mechanisms. This has led to investigations of other metal-based drug candidates such as auranofin, a gold-based drug candidate as well as ruthenium-based candidates, NAMI-A, NKP-1339 and TLD-1433. All are currently undergoing clinical trials. Another class of complexes under study are rhenium-based; such complexes have undergone extensive in vitro testing but only nine have been reported to display antitumour in vivo activity, which is a necessary step before entering clinical trials. This review will document, chronologically, the rhenium-based drug candidates that have undergone in vivo testing and the outlook for such complexes.     

Macromolecular Conjugates of 4- and 8-Aminoquinoline Compounds

Some members of 4-aminoquinolines and 8-aminoquinolines have been found to provide adjuvant effects when used in combination with anti-cancer drugs. The clinical co-administration of active anti-cancer drugs with other drugs acting as potentiating agents has shown considerable merits when compared to a single-drug administration. Anti-cancer drugs are often toxic when delivered straight, but the bio-reversible drug conjugation of anticancer drugs to water-soluble macromolecular carriers has proved to enhance the therapeutic effectiveness of anticancer drugs. Following facilitated pharmacokinetics pathways, the conjugates, acting as pro-drugs, will release the active drug species in the transformed target cells and their designs are geared towards reducing pharmacological barriers of toxicity, drug resistance and poor bioavailability encountered with currently used anti-cancer drugs. This paper describes the synthesis of water-soluble macromolecular carriers containing 4- and 8-aminoquinolines that are bio-reversibly anchored with cytotoxic drugs. The conjugates and co-conjugates are isolated as water soluble solids and characterized by NMR-spectroscopy.     

Small-molecule based delivery systems for alkylating antineoplastic compounds

Alkylating agents are a major class of anticancer drugs for the treatment of various cancers including hematological malignancies. Targeting alkylating moieties to DNA by attachment of a DNA minor groove binding carrier such as distamycin, netropsin, or Hoechst 33252 reduces the loss of active drug due to reaction with other cell components and makes it possible to direct the alkylation both sequence specifically and regiospecifically. We reported the synthesis and structure-activity studies of amidine analogues of alkylating antineoplastic compounds, which appeared to be a new class of cytotoxic minor groove binders and topoisomerase II inhibitors. Another approach to overcome the toxicity of alkylating agents to normal tissue is to construct a prodrug with lower hydrophobicity and cytotoxicity but is preferentially activated in cancer cells. Overexpression of prolidase in some neoplastic cells suggests that the proline analogue of alkylating agents may serve as a prolidase convertible prodrugs. We have compared several aspects of pharmacological actions of proline analogues of chlorambucil and melphalan in breast cancer cells. The results suggest that prolidase could serve as a target enzyme for the selective action of anticancer agents.     

Chemotherapeutic engineering: Application and further development of chemical engineering principles for chemotherapy of cancer and other diseases

This review defines chemotherapeutic engineering as an engineering discipline that applies and further develops chemical engineering principles, techniques and devices for chemotherapy of cancer and other diseases. It provides new challenges as well as new opportunities for chemical engineering. Chemical engineering has substantially changed the human civilization through its services and products to improve the quality of life for human being. It is now time for chemical engineering to contribute to the most important aspect of the quality of life—human health care. Cancer and cardiovascular diseases are the leading causes for deaths. Chemotherapy is one of the most important treatments currently available for cancer and other diseases such as cardiovascular diseases. The present status of chemotherapy is far from being satisfactory. Its efficacy is limited and patients have to suffer from serious side effects, some of which are life-threatening. Chemotherapeutic engineering is emerging to help solving the problems in chemotherapy and to eventually develop an ideal way to conduct chemotherapy with the best efficacy and the least side effects. This review gives, from an engineering point of view, brief introductions to cancer and cancer treatment, chemotherapy and the problems involved in chemotherapy, and the possible roles of chemical engineering in solving the problems involved. Progress in developing various controlled and targeted drug delivery systems is reviewed with an emphasis on nanoparticles of biodegradable polymers and lipid bilayer vesicles (liposomes). Preparation, characterization, in vitro release, cell line experiments and animal testing of drug-loaded polymeric nanoparticles are described with paclitaxel as a prototype drug, which is one of the best anticancer drugs found in nature. A novel drug delivery system, liposomes-in-microspheres, is used as an example for possible combinations of the existing polymer- and lipid-based delivery systems. Research of molecular interactions between the drug and the cell membrane is also reviewed, with the lipid monolayer at the air-water or oil-water interface and bilayer vesicles as models for the cell membrane. Finally, mathematical modeling in chemotherapeutic engineering is discussed with typical examples in the literature. This review is a short introduction of chemotherapeutic engineering to chemical engineers, biomedical engineers, other engineers, clinical oncologists, and pharmaceutical scientists, who are interested in developing new dosage forms of drugs for chemotherapy of cancer and other diseases with the best efficacy and the least side effects.     

Polymeric Co-Conjugates of Curcumin

The current cancer chemotherapy often results in high toxicity, drug resistance and some other side effects. Multidrug chemotherapy has been found to reduce the side effects associated with the currently used chemotherapy. In this research, we have demonstrated the polymer-drug co-conjugation by incorporating two bioactive agents that is, curcumin and an analogue of ferrocene (both are anticancer agents) to a polymer by a hydrazone linker. The conjugates prepared were characterized by NMR spectroscopy.     

Oncolytic activities of host defense peptides

Cancer continues to be a leading source of morbidity and mortality worldwide in spite of progress in oncolytic therapies. In addition, the incidence of cancers affecting the breast, kidney, prostate and skin among others continue to rise. Chemotherapeutic drugs are widely used in cancer treatment but have the serious drawback of nonspecific toxicity because these agents target any rapidly dividing cell without discriminating between healthy and malignant cells. In addition, many neoplasms eventually become resistant to conventional chemotherapy due to selection for multidrug-resistant variants. The limitations associated with existing chemotherapeutic drugs have stimulated the search for new oncolytic therapies. Host defense peptides (HDPs) may represent a novel family of oncolytic agents that can avoid the shortcomings of conventional chemotherapy because they exhibit selective cytotoxicity against a broad spectrum of malignant human cells, including multi-drug-resistant neoplastic cells. Oncolytic activity by HDPs is usually via necrosis due to cell membrane lysis, but some HDPs can trigger apoptosis in cancer cells via mitochondrial membrane disruption. In addition, certain HDPs are anti-angiogenic which may inhibit cancer progression. This paper reviews oncolytic HDP studies in order to address the suitability of selected HDPs as oncolytic therapies.     

Curcumin as an Enhancer of Therapeutic Efficiency of Chemotherapy Drugs in Breast Cancer

Female breast cancer is the world’s most prevalent cancer in 2020. Chemotherapy still remains a backbone in breast cancer therapy and is crucial in advanced and metastatic breast cancer treatment. The clinical efficiency of chemotherapy regimens is limited due to tumor heterogeneity, chemoresistance, and side effects. Chemotherapeutic drug combinations with natural products hold great promise for enhancing their anticancer efficacy. Curcumin is an ideal chemopreventive and chemotherapy agent owning to its multitargeting function on various regulatory molecules, key signaling pathways, and pharmacological safety. This review aimed to elucidate the potential role of curcumin in enhancing the efficacy of doxorubicin, paclitaxel, 5-fluorouracil, and cisplatin via combinational therapy. Additionally, the molecular mechanisms underlying the chemosensitizing activity of these combinations have been addressed. Overall, based on the promising therapeutic potential of curcumin in combination with conventional chemotherapy drugs, curcumin is of considerable value to develop as an adjunct for combination chemotherapy with current drugs to treat breast cancer. Furthermore, this topic may provide the frameworks for the future research direction of curcumin–chemotherapy combination studies and may benefit in the development of a novel therapeutic strategy to maximize the clinical efficacy of anticancer drugs while minimizing their side effects in the future breast cancer treatment.     

Functionalized Reduced Graphene Oxide as a Versatile Tool for Cancer Therapy

Cancer is one of the deadliest diseases in human history with extremely poor prognosis. Although many traditional therapeutic modalities—such as surgery, chemotherapy, and radiation therapy—have proved to be successful in inhibiting the growth of tumor cells, their side effects may vastly limited the actual benefits and patient acceptance. In this context, a nanomedicine approach for cancer therapy using functionalized nanomaterial has been gaining ground recently. Considering the ability to carry various anticancer drugs and to act as a photothermal agent, the use of carbon-based nanomaterials for cancer therapy has advanced rapidly. Within those nanomaterials, reduced graphene oxide (rGO), a graphene family 2D carbon nanomaterial, emerged as a good candidate for cancer photothermal therapy due to its excellent photothermal conversion in the near infrared range, large specific surface area for drug loading, as well as functional groups for functionalization with molecules such as photosensitizers, siRNA, ligands, etc. By unique design, multifunctional nanosystems could be designed based on rGO, which are endowed with promising temperature/pH-dependent drug/gene delivery abilities for multimodal cancer therapy. This could be further augmented by additional advantages offered by functionalized rGO, such as high biocompatibility, targeted delivery, and enhanced photothermal effects. Herewith, we first provide an overview of the most effective reducing agents for rGO synthesis via chemical reduction. This was followed by in-depth review of application of functionalized rGO in different cancer treatment modalities such as chemotherapy, photothermal therapy and/or photodynamic therapy, gene therapy, chemotherapy/phototherapy, and photothermal/immunotherapy.     

Carbon nanotube bottles for incorporation,release and enhanced cytotoxic effect of cisplatin

Carbon nanotubes (CNTs) have emerged as promising drug delivery systems particularly for cancer therapy, due to their abilities to overcome some of the challenges faced by cancer treatment, namely non-specificity, poor permeability into tumour tissues, and poor stability of anticancer drugs. Encapsulation of anticancer agents inside CNTs provides protection from external deactivating agents. However, the open ends of the CNTs leave the encapsulated drugs exposed to the environment and eventually their uncontrolled release before reaching the desired target. In this study, we report the successful encapsulation of cisplatin, a FDA-approved chemotherapeutic drug, into multi-walled carbon nanotubes and the capping at the ends with functionalised gold nanoparticles to achieve a “carbon nanotube bottle” structure. In this proof-of-concept study, these caps did not prevent the encapsulation of drug in the inner space of CNTs; on the contrary, we achieved higher drug loading inside the nanotubes in comparison with data reported in literature. In addition, we demonstrated that encapsulated cisplatin could be delivered in living cells under physiological conditions to exert its pharmacological action.     

Targeted Delivery of Drugs and Genes Using Polymer Nanocarriers for Cancer Therapy

Cancer is one of the primary causes of worldwide human deaths. Most cancer patients receive chemotherapy and radiotherapy, but these treatments are usually only partially efficacious and lead to a variety of serious side effects. Therefore, it is necessary to develop new therapeutic strategies. The emergence of nanotechnology has had a profound impact on general clinical treatment. The application of nanotechnology has facilitated the development of nano-drug delivery systems (NDDSs) that are highly tumor selective and allow for the slow release of active anticancer drugs. In recent years, vehicles such as liposomes, dendrimers and polymer nanomaterials have been considered promising carriers for tumor-specific drug delivery, reducing toxicity and improving biocompatibility. Among them, polymer nanoparticles (NPs) are one of the most innovative methods of non-invasive drug delivery. Here, we review the application of polymer NPs in drug delivery, gene therapy, and early diagnostics for cancer therapy.     

Synergistic Interaction of CPP2 Coupled with Thiazole Derivates Combined with Clotrimazole and Antineoplastic Drugs in Prostate and Colon Cancer Cell Lines

Cell-penetrating peptides (CPPs) are small peptide sequences used mainly as cellular delivery agents that are able to efficiently deliver cargo into cells. Some CPPs also demonstrate intrinsic anticancer properties. Previously, our group developed a new family of CPP2-thiazole conjugates that have been shown to effectively reduce the proliferation of different cancer cells. This work aimed to combine these CPP2-thiazole conjugates with paclitaxel (PTX) and 5-fluorouracil (5-FU) in PC-3 prostate and HT-29 colon cancer cells, respectively, to evaluate the cytotoxic effects of these combinations. We also combined these CPP2-thiazole conjugates with clotrimazole (CLZ), an antifungal agent that has been shown to decrease cancer cell proliferation. Cell viability was evaluated using MTT and SRB assays. Drug interaction was quantified using the Chou–Talalay method. We determined that CPP2 did not have significant activity in these cells and demonstrate that N-terminal modification of this peptide enhanced its anticancer activity in both cell lines. Our results also showed an uneven response between cell lines to the proposed combinations. PC-3 cells were more responsive to the combination of CPP2-thiazole conjugates with CLZ than PTX and were more sensitive to these combinations than HT-29 cells. In addition, the interaction of drugs resulted in more synergism in PC-3 cells. These results suggest that N-terminal modification of CPP2 results in the enhanced anticancer activity of the peptide and demonstrates the potential of CPPs as adjuvants in cancer therapy. These results also validate that CLZ has significant anticancer activity both alone and in combination and support the strategy of drug repurposing coupled to drug combination for prostate cancer therapy.