Paclitaxel Conjugate Research Articles

Ferrocene-Conjugated Paclitaxel Prodrug for Combined Chemo-Ferroptosis Therapy of Cancer.

Herein, we developed a paclitaxel prodrug (PSFc) through the conjugation of paclitaxel (PTX) and ferrocene via a redox-responsive disulfide bond. PSFc displays acid-enhanced catalytic activity of Fenton reaction and is capable of forming stable nanoparticles (PSFc NPs) through the assembly with distearoyl phosphoethanolamine-PEG2000. After being endocytosed, PSFc NPs could release PTX to promote cell apoptosis in response to overexpressed redox-active species of tumor cells. Meanwhile, the ferrocene-mediated Fenton reaction promotes intracellular accumulation of hydroxyl radicals and depletion of glutathione, thus leading to ferroptosis. Compared with the clinically used Taxol, PSFc NPs exhibited more potent in vivo antitumor outcomes through the combined effect of chemotherapy and ferroptosis. This study may offer insight into a facile design of a prodrug integrating different tumor treatment methods for combating malignant tumors.

A Practical, Scalable Synthesis of 1,18‐Octadecanedioic acid‐Paclitaxel (ODDA‐PTX)

AbstractPaclitaxel is one of the most important chemotherapy agents and it has shown activity against a variety of human cancers. In the past years several derivatives and formulations have been developed to improve its activity and reduce its toxicity. Recently, 1,18‐Octadecanedioic acid‐Paclitaxel (ODDA‐PTX), obtained by conjugation of paclitaxel with a long‐chain diacid, has emerged as a promising paclitaxel prodrug, with high efficacy and low toxicity. A novel strategy for its synthesis has been developed and is herein described. The approach is based on the mono‐allyl protection of octadecanedioic acid (ODDA) and on the Pd‐catalyzed removal of the allyl ester after coupling with paclitaxel. This strategy is superior to previously reported procedures in that it affords the ODDA‐PTX product with much higher purity, avoids chromatographic purifications and can be practically scaled‐up for the industrial production of ODDA‐PTX.

Study of drug structures using topological descriptors and multi‐criteria decision making

AbstractIt has been observed that there is a strong correlation between topological descriptors of chemical structures and their physical properties in a number of tests every year. There are several of these characteristics, including molecular mass, density, melting and boiling points, flash points, and others. Topological indices are numerical numbers associated with the molecular graph and are used in quantitative structure property relationship studies to predict their physical and chemical properties. In this work, we have calculated the reverse degree based topological descriptors of five molecular structures namely, hyaluronic acid–paclitaxel conjugates (), anticancer drug (), polyomino chain of ‐cycle (), triangular benzenoid (), and circumcoronene benzenoid series (). The values of topological indices are used in entropy method to calculate the weights. Then, using multiple criteria decision‐making techniques like COPRAS and PROMETHEE, we rank these molecular structures.

Synthesis and characterization of Fulvestrant and Paclitaxel conjugates with polyamidoamine dendrimer fourth generation

Introduction and aim. Poorly soluble anticancer drugs can be attached covalently into biologically inert macromolecule in order to administrate a drug as water soluble form. It was proven that covalent linkers, for instance amide or carbamate bonds are susceptible to hydrolysis. Thus the attached drug can be released from the conjugates in tissue, specifically within the targeted cell. We aimed at construction of water soluble conjugates of Fulvestrant and Paclitaxel with PAMAM G4 dendrimer. In order to obtain water soluble conjugates the amine groups were substituted with R-glycidol. Material and methods. Polyamidoamine dendrimer of fourth generation was synthesized and examined by detailed NMR analysis in water and in DMSO. The conjugates were covalently linked to amine groups of PAMAM after activation of Fulvestrant 17-OH group with 4-nitrophenylchloroformate and activation of end-carboxyl group of Paclitaxel succinate. Results. The method of binary conjugate PAMAMG4-Fulvestrant-Paclitaxel synthesis was elaborated and the product was characterized by physicochemical methods. Conclusion. The glycidylated PAMAMG4-Fulvestrant-Paclitaxel conjugate is better soluble in water than unconverted drugs.

Transcytosable Peptide-Paclitaxel Prodrug Nanoparticle for Targeted Treatment of Triple-Negative Breast Cancer

Triple-negative breast cancer (TNBC) is an extremely aggressive subtype associated with a poor prognosis. At present, the treatment for TNBC mainly relies on surgery and traditional chemotherapy. As a key component in the standard treatment of TNBC, paclitaxel (PTX) effectively inhibits the growth and proliferation of tumor cells. However, the application of PTX in clinical treatment is limited due to its inherent hydrophobicity, weak penetrability, nonspecific accumulation, and side effects. To counter these problems, we constructed a novel PTX conjugate based on the peptide-drug conjugates (PDCs) strategy. In this PTX conjugate, a novel fused peptide TAR consisting of a tumor-targeting peptide, A7R, and a cell-penetrating peptide, TAT, is used to modify PTX. After modification, this conjugate is named PTX-SM-TAR, which is expected to improve the specificity and penetrability of PTX at the tumor site. Depending on hydrophilic TAR peptide and hydrophobic PTX, PTX-SM-TAR can self-assemble into nanoparticles and improve the water solubility of PTX. In terms of linkage, the acid- and esterase-sensitive ester bond was used as the linking bond, with which PTX-SM-TAR NPs could remain stable in the physiological environment, whereas PTX-SM-TAR NPs could be broken and PTX be released at the tumor site. A cell uptake assay showed that PTX-SM-TAR NPs were receptor-targeting and could mediate endocytosis by binding to NRP-1. The vascular barrier, transcellular migration, and tumor spheroids experiments showed that PTX-SM-TAR NPs exhibit great transvascular transport and tumor penetration ability. In vivo experiments, PTX-SM-TAR NPs showed higher antitumor effects than PTX. As a result, PTX-SM-TAR NPs may overcome the shortcomings of PTX and present a new transcytosable and targeted delivery system for PTX in TNBC treatment.

Clathrin light chain-conjugated drug delivery for cancer.

Targeted drug delivery systems hold the remarkable potential to improve the therapeutic index of anticancer medications markedly. Here, we report a targeted delivery platform for cancer treatment using clathrin light chain (CLC)-conjugated drugs. We conjugated CLC to paclitaxel (PTX) through a glutaric anhydride at high efficiency. Labeled CLCs localized to 4T1 tumors implanted in mice, and conjugation of PTX to CLC enhanced its delivery to these tumors. Treatment of three different mouse models of cancer-melanoma, breast cancer, and lung cancer-with CLC-PTX resulted in significant growth inhibition of both the primary tumor and metastatic lesions, as compared to treatment with free PTX. CLC-PTX treatment caused a marked increase in apoptosis of tumor cells and reduction of tumor angiogenesis. Our data suggested HSP70 as a binding partner for CLC. Our study demonstrates that CLC-based drug-conjugates constitute a novel drug delivery platform that can augment the effects of chemotherapeutics in treating a variety of cancers. Moreover, conjugation of therapeutics with CLC may be used as means by which drugs are delivered specifically to primary tumors and metastatic lesions, thereby prolonging the survival of cancer patients.

Design of surface tailored carboxymethyl dextran-protein based nanoconjugates for paclitaxel: Spectroscopical characterizations and cytotoxicity assay

Paclitaxel (PTX) is an essential anticancer drug from the biopharmaceutical classification system (BCS) class IV. Unfortunately, PTX has some drawbacks including low solubility, cell toxicity, adverse cell reaction, etc. Therefore, folic acid (FA) tailored carboxymethyl-dextran (CMD), and bovine serum albumin (BSA) mediated nanoconjugates of paclitaxel (PTX) (FA-CMD-BSA-PTX) were designed. At first, esterification reaction between FA and CMD resulted in FA-CMD conjugate whereas FA-CMD-BSA conjugate was synthesized via the Maillard reaction. Finally, FA-CMD-BSA conjugates of PTX were achieved via hydrophobic interaction and gelation of BSA. Herein, heating offers the gelation of BSA that furnishes the cross-linking wherein PTX gets fixed inside BSA. Thermogram of FA-CMD-BSA-PTX showed the absence of PTX peak that concluding PTX has been molecularly dispersed in polymer matrix and entrapment inside polymeric conjugate. As an effect, surface decorated FA-CMD-BSA-PTX showed low hemolytic toxicity over free PTX. Cytotoxicity assay on A549 human lung cancer cells shows cell viability decreased from 60 % to 10 % with increasing concentration from 1 to 5 μg/mL. In conclusion, CMD facilitates the circulation time of PTX and BSA acts as a carrier to target tumor locations effectively. The nano-conjugate formulation significantly reduces toxicity and can be used for the treatment of lung cancer.

Synthesis of a Terminal Amino‐Modified Nucleolin Aptamer and Its Paclitaxel Conjugate

AbstractAptamer‐drug conjugate has been developed as a potential class of targeted therapeutics, which using aptamer as tumor recognition elements could targeted deliver the conjugated chemically toxic drug to tumor site. One of the keys to the success of aptamer‐drug conjugate is terminal modification of aptamer to facilitate the conjugation with drugs. Herein, a novel terminal amino‐modified nucleolin aptamer which using solketal as raw material was developed. Moreover, its paclitaxel conjugate wherein the aptamer coupled with paclitaxel derivatives by amidation was also conducted. The easily available raw materials, stable structure, together with its simplicity of operation, gives it the potential for use on an industrial scale.

Legumain/pH dual-responsive lytic peptide–paclitaxel conjugate for synergistic cancer therapy

After molecule targeted drug, monoclonal antibody and antibody–drug conjugates (ADCs), peptide–drug conjugates (PDCs) have become the next generation targeted anti-tumor drugs due to its properties of low molecule weight, efficient cell penetration, low immunogenicity, good pharmacokinetic and large-scale synthesis by solid phase synthesis. Herein, we present a lytic peptide PTP7-drug paclitaxel conjugate assembling nanoparticles (named PPP) that can sequentially respond to dual stimuli in the tumor microenvironment, which was designed for passive tumor-targeted delivery and on-demand release of a tumor lytic peptide (PTP-7) as well as a chemotherapeutic agent of paclitaxel (PTX). To achieve this, tumor lytic peptide PTP-7 was connected with polyethylene glycol by a peptide substrate of legumain to serve as hydrophobic segments of nanoparticles to protect the peptide from enzymatic degradation. After that, PTX was connected to the amino group of the polypeptide side chain through an acid-responsive chemical bond (2-propionic-3-methylmaleic anhydride, CDM). Therefore, the nanoparticle (PPP) collapsed when it encountered the weakly acidic tumor microenvironment where PTX molecules fell off, and further triggered the cleavage of the peptide substrate by legumain that is highly expressed in tumor stroma and tumor cell surface. Moreover, PPP presents improved stability, improved drug solubility, prolonged blood circulation and significant inhibition ability on tumor growth, which gives a reasonable strategy to accurately deliver small molecule drugs and active peptides simultaneously to tumor sites.

In Vivo Antitumor and Antimetastatic Efficacy of a Polyacetal-Based Paclitaxel Conjugate for Prostate Cancer Therapy.

Prostate cancer (PCa), one of the leading causes of cancer-related deaths, currently lacks effective treatment for advanced-stage disease. Paclitaxel (PTX) is a highly active chemotherapeutic drug and the first-line treatment for PCa; however, conventional PTX formulation causes severe hypersensitivity reactions and limits PTX use at high concentrations. In the pursuit of high molecular weight, biodegradable, and pH-responsive polymeric carriers, one conjugates PTX to a polyacetal-based nanocarrier to yield a tert-Ser-PTX polyacetal conjugate. tert-Ser-PTX conjugate provides sustained release of PTX over 2 weeks in a pH-responsive manner while also obtaining a degree of epimerization of PTX to 7-epi-PTX. Serum proteins stabilize tert-Ser-PTX, with enhanced stability in human serum versus PBS (pH 7.4). In vitro efficacy assessments in PCa cells demonstrate IC50 values above those for the free form of PTX due to the differential cell trafficking modes; however, in vivo tolerability assays demonstrate that tert-Ser-PTX significantly reduces the systemic toxicities associated with free PTX treatment. tert-Ser-PTX also effectively inhibits primary tumor growth and hematologic, lymphatic, and coelomic dissemination, as confirmed by in vivo and ex vivo bioluminescence imaging and histopathological evaluations in mice carrying orthotopic LNCaP tumors. Overall, the results suggest the application of tert-Ser-PTX as a robust antitumor/antimetastatic treatment for PCa.

Development of Tailor-Made Dendrimer Ternary Complexes for Drug/Gene Co-Delivery in Cancer.

Cancer gene therapy, mediated by non-viral systems, remains a major research focus. To contribute to this field, in this work we reported on the development of dendrimer drug/gene ternary complexes. This innovative approach explored the great capacity of both polyamidoamine (PAMAM)-paclitaxel (PTX) conjugate and polyethylenimine (PEI) polymers to complex a p53-encoding plasmid DNA (pDNA), highlighting the utility of considering two compacting agents. The pDNA complexation capacity has been investigated as function of the nitrogen to phosphate groups ratio (N/P), which revealed to be a tailoring parameter. The physicochemical properties of the conceived ternary complexes were revealed and were found to be promising for cellular transfection. Furthermore, the formulated co-delivery systems demonstrated to be biocompatible. The ternary systems were able of cellular internalization and payload intracellular release. Confocal microscopy studies showed the co-localization of stained pDNA with the nucleus of cancer cells, after transfection mediated by these carriers. From this achievement, p53 gene expression occurred with the production of protein. Moreover, the activation of caspase-3 indicated apoptosis of cancer cells. This work represents a great progress on the design of dendrimer drug/gene co-delivery systems towards a more efficient cancer therapy. In this way, it instigates further in vitro studies concerning the evaluation of their therapeutic potential, expectedly supported by the synergistic effect, in tumoral cells.

Two Decades of Triazine Dendrimers.

For two decades, methods for the synthesis and characterization of dendrimers based on [1,3,5]-triazine have been advanced by the group. Motivated by the desire to generate structural complexity on the periphery, initial efforts focused on convergent syntheses, which yielded pure materials to generation three. To obtain larger generations of dendrimers, divergent strategies were pursued using iterative reactions of monomers, sequential additions of triazine and diamines, and ultimately, macromonomers. Strategies for the incorporation of bioactive molecules using non-covalent and covalent strategies have been explored. These bioactive materials included small molecule drugs, peptides, and genetic material. In some cases, these constructs were examined in both in vitro and in vivo models with a focus on targeting prostate tumor subtypes with paclitaxel conjugates. In the materials realm, the use of triazine dendrimers anchored on solid surfaces including smectite clay, silica, mesoporous alumina, polystyrene, and others was explored for the separation of volatile organics from gas streams or the sequestration of atrazine from solution. The combination of these organics with metal nanoparticles has been probed. The goal of this review is to summarize these efforts.

Effect of XlogP and hansen solubility parameters on the prediction of small molecule modified docetaxel, doxorubicin and irinotecan conjugates forming stable nanoparticles

Small molecule-chemotherapeutic drug conjugate nanoparticles (SMCDC NPs) has a great advantage in improving drug loading. However, the factors which influence these conjugates forming stable nanoparticles (NPs) are currently unclear. In our previous studies, we synthesized a series of fatty acid-paclitaxel conjugates and suggested that the changes in the hydrophobic parameters (XlogP), solubility parameters and crystallinity of these fatty acid-paclitaxel conjugates were the key factors for affecting these small molecule-chemotherapeutic drug conjugates (SMCDCs) forming stable NPs in water. Here, we selected clinically widely used chemotherapeutic drug (docetaxel (DTX), doxorubicin (DOX) and irinotecan (Ir)) as model drug, and chose three straight-chain fatty acids (acetic acid (Ac), hexanoic acid (HA) and stearic acid (SA)) and one branched small molecule (N-(tert-butoxycarbonyl) glycine (B-G)) to synthesize 12 SMCDCs. Our results indicated that our prediction criterions obtained from paclitaxel conjugates were also appropriated for these synthesized SMCDCs. We suggested that the present studies expanded the scope of application of the above-mentioned influencing factors, provided research ideas for the rational design of SMCDC forming NPs and a basis for screening NPs with good anticancer activity.

Synthesis of Ester-Linked Paclitaxel–Glycoside Conjugate and Its Drug Delivery System Using Hybrid-Bio-Nanocapsules Targeted With Trastuzumab

Synthesis of the ester-linked glucoside conjugate of paclitaxel, 7-propionylpaclitaxel 3″- O-β-d-glucopyranoside, was carried out by chemoenzymatic procedures. The encapsulation efficiency (EE) values for hybrid-bio-nanocapsules of the compound were much improved in comparison with those of paclitaxel. The hybrid-bio-nanocapsules targeted with trastuzumab, which contained 7-propionylpaclitaxel 3″- O-β-d-glucopyranoside, showed high anticancer activity.

Improved Antiglioblastoma Activity and BBB Permeability by Conjugation of Paclitaxel to a Cell-Penetrative MMP-2-Cleavable Peptide.

In order to solve the problems of receptor promiscuity and poor blood‐brain barrier (BBB) penetration in the treatment of glioblastomas (GBM), a novel dual‐functional nanocomplex drug delivery system is developed based on the strategy of peptide‐drug conjugates. In this study, SynB3‐PVGLIG‐PTX is designed and screened out by matrix metalloproteinase‐2 (MMP‐2), to which it exhibits the best affinity. The MMP‐2‐sensitive peptide (PVGLIG) and a cell‐penetration peptide (SynB3) are combined to form a dual‐functional peptide. Moreover, as a drug‐peptide nanocomplex, SynB3‐PVGLIG‐PTX exhibited a high potential to form an aggregation with good solubility that can release paclitaxel (PTX) through the cleavage of MMP‐2. From a functional perspective, it is found that SynB3‐PVGLIG‐PTX can specifically inhibit the proliferation, migration, and invasion of GBM cells in vitro in the presence of MMP‐2, in contrast to that observed in MMP‐2 siRNA transfected cells. Further investigation in vivo shows that SynB3‐PVGLIG‐PTX easily enters the brain of U87MG xenograft nude mice and can generate a better suppressive effect on GBM through a controlled release of PTX from SynB3‐PVGLIG‐PTX compared with PTX and temozolomide. Thus, it is proposed that SynB3‐PVGLIG‐PTX can be used as a novel drug‐loading delivery system to treat GBM due to its specificity and BBB permeability.

Gold nanoparticle‑mediated delivery of paclitaxel and nucleic acids for cancer therapy (Review).

Paclitaxel is a potent antineoplastic agent, but poor solubility and resistance have limited its use. Gold nanoparticles (AuNPs) are widely studied as drug carriers because they can be engineered to prevent drug insolubility, carry nucleic acid payloads for gene therapy, target specific tumor cell lines, modulate drug release and amplify photothermal therapy. Consequently, the conjugation of paclitaxel with AuNPs to improve antiproliferative and pro-apoptotic potency may enable improved clinical outcomes. There are currently a number of different AuNPs under development, including simple drug or nucleic acid carriers and targeted AuNPs that are designed to deliver therapeutic payloads to specific cells. The current study reviewed previous research on AuNPs and the development of AuNP-based paclitaxel delivery.

An albumin-bound drug conjugate of paclitaxel and indoleamine-2,3-dioxygenase inhibitor for enhanced cancer chemo-immunotherapy

Despite the promising target of immunosuppressive enzyme indoleamine-2,3-dioxygenase (IDO) for cancer immunotherapy, IDO blockade monotherapy does not show significant benefit to cancer patients in the clinic. Recent research has focused on the combinatorial therapy of the IDO inhibitor and the immune checkpoint blockade or chemotherapy. Here, we synthesize a drug conjugate methyltryptophan-paclitaxel (MP) by linking the IDO inhibitor, D-1-methyltryptophan (D-1MT), to the chemotherapeutic agent, paclitaxel (PTX), through an ester bond. MP exhibits a similar tubulin-stabilizing effect to PTX. Like PTX, MP binds to human serum albumin to form albumin-bound MP nanoparticles (MP NPs) with a particle size of ∼115 nm in diameter. MP NPs significantly improve the tumor concentration of D-1MT due to the hydrolysis of MP in tumors. The codelivery of PTX and D-1MT offered by MP NPs in tumors significantly enhances the anti-tumor effect compared with the albumin-bound PTX NPs. Immune cell phenotyping reveals that MP NPs ameliorate the immune environment through increasing the number of the effector CD8+ T cells, and decreasing the population of regulatory T cells and granulocyte-like myeloid-derived suppressor cells. These results prove that the design of the twin drug from the IDO inhibitor and PTX synergizes the anti-tumor effect and shows promise in clinical translation.

Self-assembly of oxidation-responsive polyethylene glycol-paclitaxel prodrug for cancer chemotherapy

Amphiphilic drug conjugates can self-assemble into nanovehicles for cancer drug delivery, but the key is to design stable yet intracellular labile drug linkers for drug retention during blood circulation but fast intracellular drug release. The conjugation of paclitaxel (PTX) is generally via the ester of its 2′-hydroxyl group, but the ester is either too stable to release PTX in the cytosol or so labile that hydrolyzes during circulation. Herein, we report a p-(boronic ester)benzyl-based tumor-specifically cleavable linker for preparing PTX-conjugate with polyethylene glycol (PEG, Mw = 5000 Da) (PEG-B-PTX). The amphiphilic PEG-B-PTX self-assembled into micelle with an average size of ~50 nm and a PTX loading content of 13.3 wt%. The PEG-B-PTX micelles were very stable at the normal physiological environment and thus circulated long in the blood compartment, but fast dissociated and released PTX in response to the elevated reactive‑oxygen species (ROS) level in tumors. The conjugate micelles showed significantly improved antitumor efficiency in vitro and in vivo against human glioma and breast cancer cells, and reduced toxicity compared to the clinically used Taxol. Thus, the PTX-conjugate micelles were characteristic of well-characterized chemical structure and nanostructure, precise and reproducible drug loading efficiency (i.e., 100%) and fixed loading content, high PTX loading content due to PTX itself as part of the carrier, no burst drug release, and easy and reproducible fabrication of the micelles, which are all essential for clinical translation.

Oncofid-P-B for the treatment of BCG unresponsive carcinoma in situ (CIS) of bladder: Results of European multicenter phase I study at the end of 12- consecutive weeks intensive course.

486 Background: There is an unmet clinical need for new drugs able to delay or avoid cystectomy in patients with CIS unresponsive to BCG. Here, we report the safety and efficacy of Oncofid−P-B, is a new drug that originates from the chemical conjugation of paclitaxel with hyaluronic acid, in patients with CIS unresponsive or intolerant to BCG. Methods: This is an open-label, single arm, multicenter international study (Registered as EudraCT Number: 2016-004144-11) to assess safety, tolerability and efficacy of Oncofid-P-B administered in 20 patients with CIS, unresponsive or intolerant to BCG and unwilling or unfit for cystectomy. Oncofid-P-B was administered by intravesical instillation for 12 consecutive weeks (intensive phase). A 12 monthly (maintenance phase) in patients who were in complete response (CR) after the intensive phase is ongoing. The primary end-point was the overall safety profile. Secondary endpoints included i) efficacy after the intensive phase ii) compliance, iii) systemic absorption. The CR is defined as a negative cystoscopy including biopsy of the urothelium and negative cytology. Statistics will be calculated, as appropriate, for the quantitative variables. Results: Of the 20 enrolled patients who completed the intensive phase, CR was achieved in 15 patients (75%). Seven G1-G2 drug-related adverse events (AEs) were reported in only three patients over 240 instillations. No drug related serious AEs and no study withdrawal have been reported. In all plasma samples, the drug concentration was always below the Limit of Quantification (0.1ng/ml). Over 15 patients who ended the intensive course without CIS recurrence, five already completed the 12-month maintenance phase (four patients with no recurrence of CIS), thirteen were disease free after three months and six are completing the maintenance. Conclusions: The excellent safety profile of Oncofid-P-B is well positioned as compared with the most recent competitors, thus confirming its potential as therapeutic option in BCG unresponsive CIS patients, also with a prolonged treatment schedule, and deserves further clinical evaluation. Clinical trial information: 2016-004144-11.

DEVELOPMENT AND EVALUATION OF LOW MOLECULAR WEIGHT COMPOUNDS CONJUGATES FOR ASGPR-TARGETED DRUG DELIVERY

The conjugates of paclitaxel and betulin with N-acetylgalactosamine were obtained, their affinity to the asialoglycoprotein receptor was evaluated via surface plasmon resonance spectroscopy technique. Thermodynamic dissociation constants (KD) were determined. The influence of the structural elements of the linker on the binding of the receptor was studied.