Search

N‐alkylaminoferrocene‐based (NAAF) prodrugs are activated in the presence of reactive oxygen species (ROS), based on which these prodrugs target cancer cells (high ROS) and do not affect normal cells (low ROS). To gain some insights into their mode of action in vivo, we have investigated the biodistribution of 18F‐labelled NAAF prodrugs in tumor‐bearing mice by positron emission tomography (PET). Due to the short half‐life of 18F, the experimental time frame was restricted to 60 min. To extend the observation window, a more stable marker is required. In this paper, we report on conjugates of NAAF prodrugs with two cyanine dyes Cy5 and Cy7 including details of their synthesis, characterization and basic properties in cell free settings and their cellular uptake in representative human cancer cells. Finally, the Cy5 conjugate was subjected to in vivo fluorescence imaging studies to determine the prodrug biodistribution over 24 h.

The longstanding notion that Pt(IV) complexes are inert under physiological conditions where there are limited reducing agents is facing a great challenge. Herein, we systematically investigated the hydrolytic stability of a wide range of unsymmetric Pt(IV) anticancer prodrugs built upon clinical Pt(II) drugs. The detailed structure–stability relationship shows that the hydrolytic stability of one certain axial ligand in Pt(IV) complexes can be dramatically affected by the other five ligands; both the coordination environment of equatorial ligands and the “trans influence” from one axial ligand affect the hydrolytic stability of the counter axial ligand, and the more electronegative axial ligand faces the higher possibility to detach. Inspiringly, this newly discovered structure–stability relationship has been successfully applied to improve the hydrolytic stability of Pt(IV) complexes that contain axial dichloroacetato ligands. Our discovery represents a significant advancement in the theory of the chemical inertness of Pt(IV) complexes toward ligand exchange reactions and provides a practical guide for the future design of Pt(IV) anticancer prodrugs.

We would like to be able to design Pt(IV) prodrugs that can overcome resistance and minimize side effects. Unlike with the early exploration of Pt(II) anticancer agents where clear structure-activity relationships were defined, even after more than two decades of research on Pt(IV) prodrugs, there is no roadmap that can point us to the holy grail. Despite many excellent rational endeavors, we still have not found the "right" two axial ligands to append to the Pt(IV) derivatives of platinum(II) drugs that will "make platinum great again". So far this proved elusive, indicating that the design of Pt(IV) prodrugs is a difficult and frustrating task. Despite our better understanding of the biological processes and availability of advanced technologies, even our sophisticated rational plans often leave us disappointed and frustrated because at the end of the day, we are not able to outsmart the cancer cells or the mice, and just like Rosenberg, we might need to be rescued by serendipity.

Anticancer prodrugs have been extensively investigated to lower toxic side effects of common chemotherapeutic agents in biomedical fields. To illustrate the activation mechanism of anticancer prodrugs, fluorescent dyes or single-emission intensity alteration-based approaches have been widely used. However, fluorescent dyes often suffer from poor photostability and chemical stability, and single-emission intensity alteration-based methods cannot avoid the influence from uncontrolled microenvironment changes in living samples. To overcome these obstacles, herein, a fluorescence resonance energy transfer (FRET)-based ratiometric approach was successfully developed for real-time monitoring of anticancer prodrug activation. Excitation-wavelength-dependent and full-color-emissive carbon dots (CDs) were used as drug nanocarriers and FRET donor, and a cisplatin(IV) prodrug was selected as the model drug and the linker to load the Dabsyl quencher on the surface of CDs. Owing to the FRET effect, the blue fluorescence of CDs was effectively quenched by the Dabsyl unit. Under reductive conditions in solution or in living cells for the reduction of cisplatin(IV) prodrug to Pt(II) species, the blue fluorescence of CDs increased over time, without apparent intensity change for green or red fluorescence. Thus, the gradually enhanced intensity ratio of blue-to-green or blue-to-red fluorescence could be indicative of the real-time reduction of the cisplatin(IV) prodrug to cytotoxic Pt(II) species. This ratiometric method could exclude the influence from complex biological microenvironments by using green or red fluorescence of CDs as an internal reference, which provides new insights into the activation of the cisplatin(IV) prodrug and offers a great opportunity to design safe and effective anticancer therapeutics.

Platinum-based anticancer drugs have been widely applied in clinical settings for more than 40 years. The remarkable breakthroughs that have come from the use of these complexes in cancer therapy have stimulated a continual search for new platinum anticancer drugs. The most promising result of these efforts is a prodrug strategy based on the use of platinum(IV) versions of the traditional platinum(II) anticancer drugs. Hence, the design of synthetic methods for platinum(IV) prodrugs and an understanding of their hydrolytic stability and intracellular activation processes are critical for the development of platinum(IV) prodrugs for cancer therapy. In this review, we summarize recent progress in this field from a comprehensive viewpoint, with an emphasis first on the oxidation processes in chemical environments where platinum(II) compounds are converted to their platinum(IV) species, followed by the reduction processes in biological environments where platinum(IV) species are converted back to platinum(II) forms. First, recent approaches that use new oxidizing reagents to synthesize platinum(IV) prodrugs are summarized, and the oxidation mechanisms and outer-sphere functionalization of platinum(IV) prodrugs are examined. Second, the hydrolysis of platinum(IV) complexes, which has sometimes been underexplored, is discussed, and the factors associated with the hydrolytic stability of platinum(IV) complexes are reviewed. Last, we focus on the reduction of platinum(IV) prodrugs, from the perspectives of reduction potential, rate of reduction, reducing agents, and reduction products. The need for new strategies to achieve controllable intracellular reduction of platinum(IV) prodrugs is emphasized. This review aims to help researchers to improve their understanding of platinum(IV) anticancer prodrugs and hopefully to generate new ideas, strategies, and applications in the area of metal-based drugs.

Diazido Pt(IV) complexes with a general formula [Pt(N3)2(L)(L′)(OR)(OR′)] are a new generation of anticancer prodrugs designed for use in photoactivated chemotherapy. The potencies of these complexes are affected by the cis/trans geometry configuration, the non-leaving ligand L/L′ and derivatisation of the axial ligand OR/OR′. Diazido Pt(IV) complexes exhibit high dark stability and promising photocytotoxicity circumventing cisplatin resistance. Upon irradiation, diazido Pt(IV) complexes release anticancer active Pt(II) species, azidyl radicals and ROS, which interact with biomolecules and therefore affect the cellular components and pathways. The conjugation of diazido Pt(IV) complexes with anticancer drugs or cancer-targeting vectors is an effective strategy to optimise the design of these photoactive prodrugs. Diazido Pt(IV) complexes represent a series of promising anticancer prodrugs owing to their novel mechanism of action which differs from that of classical cisplatin and its analogues.

High specificity detection and site-specific therapy are still the main challenges for theranostic anticancer prodrugs. In this work, we reported two smart activatable theranostic molecules based on a thermally activated delayed fluorescence fluorescein derivative. Nitroreductase induced by a mild hypoxia microenvironment of a solid tumor was used to activate the fluorescence and photodynamic therapy (PDT) efficiency by employing the intramolecular photoinduced electron transfer mechanism. A high PDT efficiency under 10% oxygen concentration was achieved, which is better than that of porphyrin (PpIX), a traditional photosensitizer. Such an excellent PDT efficiency can be attributed to lysosome disruption because the theranostic molecule can specifically enter the lysosomes of cells. Importantly, the strategy of targeting the mild hypoxic cells in the edge of tumor tissue could heal the "Achilles' heel" of traditional PDT. We believe that this theranostic molecule has a high potential to be applied in clinical investigation as a theranostic anticancer prodrug.

The reduction mechanism of Pt(IV) anticancer prodrugs, still today a matter of debate, assisted by one of the dominant reductants in human plasma, that is l-ascorbic acid in its monodeprotonated form, has been computationally examined in this work. In order to check what should be the influence on the reduction rate of the identity of the ligands in axial and equatorial position, both cisplatin and oxaliplatin derivatives have been studied, varying the ligands in axial position in connection with the role they should play as bridges, trans leaving species, and proton acceptors. OH, OAc, Cl, and Br ligands have been tested as bridging/leaving ligands, whereas Cl and aspirin have been used as trans labile and less labile ligands, respectively. The most recent theoretical and experimental investigations have demonstrated that the generally adopted grouping of reduction mechanisms into inner- and outer-sphere does not properly take into account all the viable alternatives. Therefore, inner-sphere mechanisms, classified as ligand-bridged, ligand-bridged-H transfer and enolate β-carbon attack, have been explored for all the complexes under investigation. Concerning the outer-sphere mechanism, redox potentials have been calculated adopting a recently proposed procedure based on the separation between electrochemical and chemical events to evaluate their propensity to be reduced. Moreover, according to the hypothesis that the outer-sphere reduction mechanism involves the sequential addition of two electrons causing the formation of a Pt(III) intermediate, the possibility that singlet and triplet pathways can cross for the Pt(IV) cisplatin derivative having two chlorido ligands in axial position has been explored in detail. Results show that the mechanism indicated as base-assisted outer sphere can become competitive with respect to the inner one if two singlet-triplet spin inversions occur. Results presented here are helpful in addressing synthetic strategies as they show that Pt(IV) prodrugs propensity to be reduced can be properly tuned and give indications on how this aim can be accomplished.

Boronic acid (and ester) prodrugs targeting the overexpressed level of reactive oxygen species within tumor microenvironment represent a promising area for the discovery of new selective anticancer chemotherapy. This strategy that emerged only ten years ago is exponentially growing and could demonstrate its clinical usefulness in the near future. Herein, the previously described small-molecule and macromolecular anticancer prodrugs activated by carbon-boron oxidation are gathered. This review reports on the most interesting derivatives mentioned in the literature based on the in vitro and in vivo activity when available. Eventually, the pharmacological applicability of this strategy is discussed, in particular, the kinetic aspect of the prodrug oxidation and the selectivity of this reaction towards certain ROS from the tumor microenvironment are specified.

Human serum albumin (HSA) is the most abundant protein in the plasma. HSA plays a central role in drug pharmacokinetics because most drugs bound to HSA are delivered to their target organ/tissues. The prodrug strategies have shown great promise for improving the activity and selectivity of drugs. Designing prodrugs based on special HSA residues, such as Cys34 and Lys residues, has been extensively studied. Therefore, this review provides an overview of the development of nonsteroidal anti-inflammatory and anticancer prodrugs based on these special residues. In conclusion, this review may guide the rational design and development of new prodrugs for future clinical applications.

A novel 5-fluorouracil (5-FU)-based anticancer prodrugs consisting of pyrene and oligonucleotide trimer having 5-halouracils were designed. The UVA-induced electron injection from photoexcited pyre...

Solid lipid nanoparticles (SLNs) comprise a versatile drug delivery system that has been developed for the treatment of a variety of diseases. The present study will investigate the feasibility of entrapping an active doxorubicin prodrug (a squalenoyl-derivative) in SLNs. The doxorubicin derivative-loaded SLNs are spherically shaped, have a mean diameter of 300-400 nm and show 85% w/w drug entrapment efficiency. The effects on cell growth of loaded SLNs, free doxorubicin and the prodrug have been examined using cytotoxicity and colony-forming assays in both human ovarian cancer line A2780 wild-type and doxorubicin-resistant cells. Further assessments as to the treatment's ability to induce cell death by apoptosis have been carried out by analyzing annexin-V staining and the activation of caspase-3. The in vitro data demonstrate that the delivery of the squalenoyl-doxorubicin derivative by SLNs increases its cytotoxic activity, as well as its apoptosis effect. This effect was particularly evident in doxorubicin-resistant cells.

The review describes two major groups of α-amino acid ester hydrolases (AEHs)—enzymes with a similar active center structure, which determines their unique specificity to esters containing an amino group in the α position to the carbonyl. The first group comprises microbial AEHs of the β-lactam acylase type. Technical biocatalysts based on this group of enzymes are used for the production of semi-synthetic amino-β-lactam antibiotics. The second AEH group includes eukaryotic valacyclovirases, which activate in vivo a number of antiviral and anticancer prodrugs. The directed activity of these enzymes is used for the development of target pharmaceutical preparations for the therapy of viral and oncological diseases. The review summarizes and compares the available data on the structure and properties, substrate specificity, and the kinetic parameters of enzymes of these two groups. Experiments identifying the AEH active site and providing the molecular basis for the unique specificity of these enzymes are discussed. The data from the available scientific and patent publications concerning the aminopenicillin and aminocephalosporin synthesis catalyzed by β-lactam acylase AEHs are reviewed and systematized.

A novel approach to design bimetallic anticancer drug candidates with the capability to combat both drug resistance and tumor metastasis is reported. These water-soluble bifunctional Pt(IV)–Ru(II) heterodinuclear complexes with a unique mode of action display up to 2-orders of magnitude enhanced cytotoxicity in cisplatin-resistant cells and significantly impede cancer cell migration.

Most anticancer drugs have poor aqueous solubility and low permeability across the gastrointestinal tract. Furthermore, extensive efflux by P-glycoproteins (P-gp) in the small intestine also limits the efficient delivery of anticancer drugs via oral route. Area covered: This review explores the prodrug strategy for oral delivery of anticancer drugs. Different categories of oral anticancer prodrugs along with recent clinical studies have been comprehensively reviewed here. Furthermore, novel anticancer prodrugs such as polymer-prodrugs and lipid-prodrugs have been discussed in detail. Finally, various nanocarrier-based approaches employed for oral delivery of anticancer prodrugs have also been discussed. Expert opinion: Premature degradation of anticancer prodrugs in the gastrointestinal tract could lead to variable pharmacokinetics and undesired toxicity. Despite their increased aqueous solubility, the oral bioavailability of several anticancer prodrugs are limited by their poor permeability across the gastrointestinal tract. These limitations can be overcome by the use of functional excipients (polymers, lipids, amino acids/dipeptides), which are specifically absorbed via transporters and receptor-mediated endocytosis. Oral delivery of anticancer prodrugs using nanocarrier-based drug delivery system is a recent development; however it should be justified based on the comparative advantages of encapsulating prodrug in a nanocarrier versus the use of anticancer prodrug molecule itself.

In this manuscript we focus on Pt(iv) anticancer prodrugs. We explore the main working hypotheses for the design of effective Pt(iv) prodrugs and note the exceptions to the common assumptions that are prevalent in the field. Special attention was devoted to the emerging class of "dual action" Pt(iv) prodrugs, where bioactive ligands are conjugated to the axial positions of platinum in order to obtain orthogonal or complementary effects that will increase the efficacy of killing the cancer cells. We discuss the rationale behind the design of the "dual action" prodrugs and the results of the pharmacological studies obtained. Simultaneous release of two bioactive moieties inside the cancer cells often triggers several processes that together determine the fate of the cell. Pt(iv) complexes provide many opportunities for applying new concepts in targeting, synergistic cell killing and exploiting novel nanodelivery systems.

Platinum(II) anticancer drug cisplatin is one of the most important chemotherapeutic agents in clinical use but is limited by its high toxicity and severe side effects. Platinum(IV) anticancer prodrugs can overcome these limitations by resisting premature aquation and binding to essential plasma proteins. Structure-activity relationship studies revealed a link between the efficacy of platinum(IV) complexes with the nature of their axial ligands, which can be modified to enhance the properties of the prodrug. The existing paradigm of employing platinum(IV) complexes with symmetrical axial carboxylate ligands does not fully exploit their vast potential. A new approach was conceived to control properties of platinum(IV) prodrugs using contrasting axial ligands via sequential acylation. We report a novel class of asymmetric platinum(IV) carboxylates based on the cisplatin template containing both hydrophilic and lipophilic ligands on the same scaffold designed to improve their aqueous properties and enhance their efficacy against cancer cells in vitro.

The serendipitous discovery of the antitumor properties of cisplatin by Barnett Rosenberg some forty years ago brought about a paradigm shift in the field of medicinal chemistry and challenged conventional thinking regarding the role of potentially toxic heavy metals in drugs. Platinum(II)-based anticancer drugs have since become some of the most effective and widely-used drugs in a clinician's arsenal and have saved countless lives. However, they are limited by high toxicity, severe side-effects and the incidence of drug resistance. In recent years, attention has shifted to stable platinum(IV) complexes as anticancer prodrugs. By exploiting the unique chemical and structural attributes of their scaffolds, these platinum(IV) prodrugs offer new strategies of targeting and killing cancer cells. This review summarizes the development of anticancer platinum(IV) prodrugs to date and some of the exciting strategies that utilise the platinum(IV) construct as targeted chemotherapeutic agents against cancer.

Over the past four decades, the search for improved platinum drugs based on the classical platinum (II)-diam(m)ine pharmacophore has yielded only a handful of successful candidates. New methodologies centred on platinum (IV) complexes, with better stability and expanded coordination spheres, offer the possibility of overcoming limitations inherent to platinum (II) drugs. In this review, novel strategies of targeting and killing cancer cells using platinum (IV) constructs are discussed. These approaches exploit the unique electrochemical characteristics and structural attributes of platinum (IV) complexes as a means of developing anticancer prodrugs that can target and selectively destroy cancer cells. Anticancer platinum (IV) prodrugs represent promising new strategies as targeted chemotherapeutic agents in the ongoing battle against cancer.

A series of phosphate or phosphate–acetate hybrid modified EGCG or EGCG G ring deoxy analogs were synthesized by a convenient semi-synthesis strategy from the abundant natural compound EGCG.

Research in anticancer chemotherapy has produced outstanding results, and mean survival rates have significantly improved over the last ten years. Nevertheless, all approved drugs are still characterized by narrow therapeutic windows that result mainly from their high systemic toxicity combined with their marked lack of tumor selectivity. Medicinal chemistry responds to the resulting demands with new analogues of a lead drug, or by developing prodrugs. Prodrugs are inactive compounds, which are metabolized in the body, either chemically or enzymatically, in a controlled or predictable manner, to the active parent drug. This review describes the results of strategies in prodrug development, subdivided into the principal categories of anticancer agents. The chemical implementation of prodrug approaches is illustrated through selected drug candidates.

Triptorelin (TRP) and Leuprorelin (LEP) are two synthetic analogue of gonadotropin-releasing hormone (GnRH), first was approved by the FDA for treatment of advanced prostate cancer and endometriosis in mid 80s. The surge of testosterone, known as a flare effect, is the major side-effect of cancer chemotherapy using TRP and LEP in a combination regiment. Therefore, improving of the biological activity of TRP and LEP by increasing the cellular uptake and retention is a remedy to this end.In this research, polyphenolic derivatives were linked to TRP and LEP through hydrophobic linkers to enhance and optimize the hydrophobicity of these drugs with the expectation to improve the cellular uptake. In this regard, several TRP and LEP conjugates of tris(4-methoxyphenyl)methanol (TPM) derivatives with optimized hydrophobicity were synthesized by the reaction of methoxy benzenes (e.g. methyl 2-methoxybenzoate, 1,2-dimethoxybenzene, methoxy-2-methylbenzene, methoxy-2-nitrobenzene, chloro-2-methxyenzene, anisole, 2-fluoroanisole or 2-methylanisole and 1,3,5-trioxane, followed by the conjugation with TRP or LEP and decanedioic acid or dodecanedioic acid in the presence of HBTU/DIPEA/DIC in moderate yields.Comparative antiproliferative assays between TPM-TRP conjugates and the corresponding non-covalent physical mixtures of the TPM derivatives and TRP were performed against human acute lymphoblastic leukemia (CCRF-CEM), human ovarian adenocarcinoma (SK-OV-3), and mouse pre adipocytes (3T3-L1) cells. TPM-TRP conjugates inhibited the cell proliferation of CCRF-CEM, SK-OV-3 and 3T3-L1 cells by 55-92%, 24-73%, 37-56%, respectively, at a concentration of 10-50 µM after 24-72 h of incubation. Similar antiproliferative assays between TPM-LEP conjugates and the corresponding non-covalent physical mixtures of the TPM derivatives and LEP were performed against human Caucasian prostate adenocarcinoma (PC3), human breast cancer cell line (BT549) and mouse pre-adipocytes (3T3-L1) cells and indicated moderare to high inhibition of the cell proliferation at a concentration of 5-100 µM after 24-72 h of incubation. These data suggest that TPM-TRP and TPM-LEP derivatives with optimized hydrophobicity can be used to improve the biological activity of TRP or LEP. Citation Format: Yousef Beni, Samiyah Alhamed, Jawzah Alnakhli, Kaleh Karim, William Boadi. Polyphenolic triptorelin and leuprorelin derivatives as anticancer prodrugs [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2686.

To increase the therapeutic index of chemotherapeutic drugs, prodrugs have been investigated as anticancer agents, as they may present fewer cytotoxic side effects than conventional cytotoxic drugs, while therapeutic efficacy is maintained or even increased. Extracellular beta-glucuronidase (beta-GUS) in the tumors has been investigated as a target enzyme for prodrug therapy, as it can convert nontoxic prodrugs into cytostatic drugs. To optimize beta-GUS-based prodrug therapies, PET imaging could be a useful tool by providing information regarding the localization and quantification of beta-GUS. Here, we describe our first PET tracer for extracellular beta-GUS, [(18)F]-FEAnGA, which consists of a 2-[(18)F]fluoroethylamine ([(18)F]-FEA) group bound to a glucuronic acid via a self-immolative nitrophenyl spacer. [(18)F]-FEAnGA was synthesized by alkylation of its imidazole carbamate precursor with [(18)F]-FEA, followed by deprotection of the sugar moiety with NaOH in 10-20% overall radiochemical yield. [(18)F]-FEAnGA is about 10-fold more hydrophilic than the cleavage product [(18)F]-FEA, and it is stable in PBS and rat plasma for at least 3 h. In the presence of either Escherichia coli beta-GUS or bovine liver beta-GUS, in vitro cleavage of [(18)F]-FEAnGA with complete release of [(18)F]-FEA was observed within 30 min. C6 glioma cells incubated with the tracer and Escherichia coli beta-GUS or bovine liver beta-GUS showed a 4- and 1.5-fold higher uptake of radioactivity, respectively, as compared to control C6 cells without beta-GUS. Incubation of CT26 murine colon adenocarcinoma cells or the genetically engineered CT26mbetaGUS cells, which expressed membrane-anchored GUS on the outer cell membrane, with the tracer, resulted in a 3-fold higher uptake into GUS-expressing cells as compared to control cells. In a preliminary microPET study in mice bearing both CT26 and CT26mbetaGUS tumors, [(18)F]-FEAnGA exhibited a 2-fold higher retention of radioactivity in the tumor expressing beta-GUS than in the control tumor. [(18)F]-FEA did not show any difference in tracer uptake between tumors. These results suggest that [(18)F]-FEAnGA may be a suitable PET tracer for evaluation of beta-GUS activity, since it is specifically cleaved by beta-GUS and the released [(18)F]-FEA remains attached to targeted cells.

A model for light-triggered porphyrin anticancer prodrug 1 was designed and synthesized. Upon photolysis, prodrug 1 can efficiently liberate the anticancer drug tegafur. The MTT assay demonstrates that prodrug 1 is significantly less toxic than its parent drug tegafur, and 1 can release tegafur upon photoactivation in vitro. The light-triggered porphyrin anticancer prodrug technique developed herein may find useful applications in chemotherapy to minimize the side effects of anticancer drugs because of the tumor affinity property of porphyrin and the light-controllable anticancer drug dosing. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2008)

Reduction of anticancer prodrugs such as ctc-[PtCl(2)(CH(3)CO(2))(2)(NH(3))(Am)] can yield three products in addition to the expected cis-[PtCl(2)(NH(3))(Am)]. A possible explanation is that reduction proceeds by several pathways where in addition to the loss of two axial ligands, one axial (acetato) and one equatorial (chlorido) ligand, or two equatorial ligands are eliminated.

We evaluated the effects of the benzylic leaving group and core structure of arylboronates on H2O2-induced formation of bisquinone methides for DNA interstrand cross-linking. The mechanism of DNA cross-linking induced by these arylboronates involves generation of phenol intermediates followed by departure of benzylic leaving groups leading to QMs which directly cross-link DNA via alkylation. The QM formation is the rate-determining step for DNA cross-linking. A better leaving group (Br) and stepwise bisquinone methide formation increased interstrand cross-linking efficiency. These findings provide essential guidelines for designing novel anticancer prodrugs.

Prodrugs and their polymeric conjugates (transport forms) offer many promising modalities for new cancer chemotherapies. They present unique opportunities to increase the therapeutic index of a particular drug by exploiting the properties associated with the disease in a predictable fashion. Drugs can be chemically modified with a promoiety to achieve an exclusive selectivity by utilising specific enzymes, fenestrated vasculatures, more acidic environments and other unique properties of the tumour. Additionally, by incorporating a promoiety into existing immunoconjugates, greater efficacy can be achieved.

Chemotherapy has been performed to treat metastatic cancers but with varying degrees of success. The optimal potential of chemotherapy has not been achieved yet. Numerous compounds cannot be further developed to produce potent drugs because these compounds exhibit poor druggability. To resolve this issue, researchers developed prodrugs in drug discovery because these drugs can be efficiently used. Many small-molecule prodrugs have been designed and synthesized as anticancer agents for several years, and great progress has been achieved. In this study, recently developed, efficient anticancer prodrugs were reviewed, particularly small molecule prodrugs. Moreover, small molecule anticancer prodrugs were summarized according to different types of chemical structures and properties.

Targeting tumor cells is an important strategy to improve the selectivity of cancer therapies. With the advanced studies in cancer biology, we know that cancer cells are usually under increased oxidative stress. The high level of reactive oxygen species in cancer cells has been exploited for developing novel therapeutic strategies to preferentially kill cancer cells. Our group, amongst others, have used boronic acids/esters as triggers for developing ROS-activated anticancer prodrugs that target cancer cells. The selectivity was achieved by combining a specific reaction between boronates and H2O2 with the efficient masking of drug toxicity in the prodrug via boronates. Prodrugs activated via ferrocene-mediated oxidation have also been developed to improve the selectivity of anticancer drugs. We describe how the strategies of ROS-activation can be used for further development of new ROS-targeting prodrugs, eventually leading to novel approaches and/or combined technology for more efficient and selective treatment of cancers.

Prodrugs are inactive compounds which are metabolized in the body to produce parent active agents. It has been shown that prodrugs hold some advantages over conventional drugs, such as increased solubility, improved permeability and bioavailability, reduced adverse effects and prolonged half-lives. Optimization of the vehicles used is very important in order to employ the advantages of prodrugs. Nanocarriers are currently being widely used as prodrug vehicles because of their ability to enhance storage stability, modulate prodrug release and tumor-targeted delivery and protect against enzymatic attack. This combined approach of prodrugs and nanoparticles has a particular attraction for developing anticancer therapies.This paper discusses liposomes, polymeric nanoparticles and lipid nanoparticles, which are all carriers commonly used for prodrug encapsulation. Macromolecular prodrugs can spontaneously form self-assembled nanoparticles with no intervention of other additives. This review also describes recent developments in prodrug delivery using nanoparticulate strategies. Pharmacokinetic, pharmacodynamic and cytotoxicity evaluations of anticancer prodrugs are systematically elucidated in this review.More profiles involved in animal and clinical studies will encourage the future applicability of prodrug nanocarrier therapy. The possible toxicity associated with nanoparticles is a concern for development of prodrug delivery.

There are numerous anticancer agents based on a prodrug approach. However, no attempt has been made to review the ample available literature with a specific focus on the altered cell uptake pathways enabled by the conjugation and on the intracellular drug-release mechanisms. This article focuses on the cellular interactions of a broad selection of parenterally administered anticancer prodrugs based on synthetic polymers, proteins or lipids. The report also aims to highlight the prodrug design issues, which are key points to obtain an efficient intracellular drug delivery. The chemical basis of these molecular concepts is put into perspective with the uptake and intracellular activation mechanisms, the in vitro and in vivo proofs of concepts and the clinical results. Several active targeting strategies and stimuli-responsive architectures are discussed throughout the article.

Ligand-targeted therapeutics have increased in prominence because of their potential for improved potency and reduced toxicity. However, with the advent of personalized medicine, a need for greater versatility in ligand-targeted drug design has emerged, where each tumor-targeting ligand should be capable of delivering a variety of therapeutic agents to the same tumor, each therapeutic agent being selected for its activity on a specific patient's cancer. In this report, we describe the use of a prostate-specific membrane antigen (PSMA)-targeting ligand to deliver multiple unrelated cytotoxic drugs to human prostate cancer (LNCaP) cells. We demonstrate that the PSMA-specific ligand, 2-[3-(1, 3-dicarboxy propyl)ureido] pentanedioic acid, is capable of mediating the targeted killing of LNCaP cells with many different therapeutic warheads. These results suggest that flexibility can be designed into ligand-targeted therapeutics, enabling adaptation of a single targeting ligand for the treatment of patients with different sensitivities to different chemotherapies.