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Current Medicinal Chemistry 2021Paclitaxel (PTX) is the first natural plant-derived chemotherapeutic drug approved by the Food and Drug Administration. However, the clinical applications of PTX are... (Review)
Review
Paclitaxel (PTX) is the first natural plant-derived chemotherapeutic drug approved by the Food and Drug Administration. However, the clinical applications of PTX are limited by some drawbacks, such as poor water solubility, rapid blood clearance, nonspecific distribution, and adverse side effects. Nanocarriers have made important contributions to drug delivery and cancer therapy in recent years. However, low drug loading capacity, nanocarrier excipients-induced toxicity or immunogenicity, and complicated synthesis technologies pose a challenge for the clinical application of nanocarriers. To address these issues, the self-delivery nanomedicine (SDNs), in which pure drug molecules directly self-assemble into nanomedicine, have been developed for drug delivery and enhancing antitumor efficacy. In this review, we comprehensively summarize the recent advances in PTX-based SDNs for cancer therapy. First, the self-assembly strategies to develop pure PTX nanodrugs are discussed. Then, the emerging strategies of co-assembly PTX and other therapeutic agents for effective combination therapy are presented, composing of combination chemotherapy, chemo-photothermal therapy, chemo-photodynamic therapy, chemo-immunotherapy, and chemo-gene therapy. Finally, the limitations and future outlook of SDNs are discussed. The rational design of these unique nanoplatforms may make a new direction to develop highly efficient drug delivery systems for cancer therapy.
Topics: Cell Line, Tumor; Drug Delivery Systems; Drug Therapy, Combination; Humans; Nanomedicine; Nanoparticles; Neoplasms; Paclitaxel
PubMed: 33176629
DOI: 10.2174/0929867327666201111143725 -
BMC Pharmacology & Toxicology Mar 2023Albumin-bound paclitaxel (nab-paclitaxel), as a special targeted preparation of paclitaxel, has the advantages of good curative effect and less side effects in...
BACKGROUND
Albumin-bound paclitaxel (nab-paclitaxel), as a special targeted preparation of paclitaxel, has the advantages of good curative effect and less side effects in anti-tumor therapy. The existence of the plasma-peritoneal barrier and insufficient blood supply make intravenous drugs hard to reach the peritoneum, while hyperthermic intraperitoneal chemotherapy can solve the difficulty. And compared with systemic medications, HIPEC can also give higher concentrations of chemotherapy drugs in the abdominal cavity, while ensuring lower systemic toxicity. However, at present, there is no relevant report on the clinical study of nab-paclitaxel during intraperitoneal hyperthermic chemotherapy, and its stability under special temperature conditions has not been reported either.
METHODS
In this study, We examined three batches of albumin-bound paclitaxel dissolved in saline at different temperatures (25 °C, 37 °C, 41 °C, 42 °C and 43 °C) for the changes of human serum albumin content, human serum albumin polymer content, related substance content, in-vitro release rate, paclitaxel binding rate and paclitaxel content at different temperatures.
RESULTS
Our results demonstrated that the indicators including human serum albumin content, human serum albumin polymer content, in-vitro release rate, paclitaxel binding rate and paclitaxel content were stable to the several temperatures, except that Taxane (0.1%) and other individual impurities in the determination of related substance content fluctuated comparatively widely with the change of temperature. In addition, only Taxane (0.1%) and 7-Epitaxol (1%) were detected.
CONCLUSIONS
Overall, albumin-bound paclitaxel is relatively stable to different temperatures (25 °C, 37 °C, 41 °C, 42 °C and 43 °C). This study will lay a foundation for further studies on the albumin-bound paclitaxel during hyperthermic intraperitoneal chemotherapy.
Topics: Humans; Albumin-Bound Paclitaxel; Hyperthermic Intraperitoneal Chemotherapy; Paclitaxel; Taxoids; Serum Albumin, Human; Polymers
PubMed: 36859304
DOI: 10.1186/s40360-023-00653-2 -
Molecules (Basel, Switzerland) Nov 2023Paclitaxel, a natural secondary metabolite isolated and purified from the bark of the tree, is considered one of the most successful natural anticancer drugs due to its... (Review)
Review
Paclitaxel, a natural secondary metabolite isolated and purified from the bark of the tree, is considered one of the most successful natural anticancer drugs due to its low toxicity, high potency and broad-spectrum anticancer activity. trees are scarce and slow-growing, and with extremely low paclitaxel content, the contradiction between supply and demand in the market is becoming more and more intense. Therefore, researchers have tried to obtain paclitaxel by various methods such as chemical synthesis, artificial culture, microbial fermentation and tissue cell culture to meet the clinical demand for this drug. This paper provides a comprehensive overview of paclitaxel extraction, combination therapy, total synthesis, semi-synthesis and biosynthesis in recent years and provides an outlook, aiming to provide a theoretical basis and reference for further research on the production and application of paclitaxel in the future.
Topics: Paclitaxel; Fermentation; Taxus
PubMed: 38005238
DOI: 10.3390/molecules28227517 -
Carbohydrate Polymers Sep 2022Paclitaxel, a clinical chemotherapy drug commonly used in the past few years, is greatly limited by its low therapeutic index. Starch and its derivatives have gained... (Review)
Review
Paclitaxel, a clinical chemotherapy drug commonly used in the past few years, is greatly limited by its low therapeutic index. Starch and its derivatives have gained wide interest from researchers owing to their unique hydrophilic and hydrophobic properties resulting from their various modifications, which exert the effect-enhancing and toxicity-reducing activity to paclitaxel in vivo and in vitro. This review summarizes the research progress toward different kinds of starch-based carriers, whether oral or injectable. In addition, we discuss the complex properties of starch derivatives toward physically complexed or chemically conjugated paclitaxel. The corresponding complex configurations are suggested. Starch-based carriers can act as permeability enhancers because they may interact with the unstirred water layer that separates hydrophobic drugs from biological membranes, even altering the barrier properties of the membrane. The information presented in this review may be used as a reference for future hydrophobic drug carrier studies.
Topics: Drug Carriers; Excipients; Hydrophobic and Hydrophilic Interactions; Paclitaxel; Starch
PubMed: 35698420
DOI: 10.1016/j.carbpol.2022.119628 -
Chembiochem : a European Journal of... Oct 2023Co-delivery of anticancer drugs and target agents by endogenous materials is an inevitable approach towards targeted and synergistic therapy. Employing DNA base pair...
Co-delivery of anticancer drugs and target agents by endogenous materials is an inevitable approach towards targeted and synergistic therapy. Employing DNA base pair complementarities, DNA nanotechnology exploits a unique nanostructuring method and has demonstrated its capacity for nanoscale positioning and templated assembly. Moreover, the water solubility, biocompatibility, and modifiability render DNA structure suitable candidate for drug delivery applications. We here report single-stranded DNA tail conjugated antitumor drug paclitaxel (PTX), and the co-delivery of PTX, doxorubicin and targeting agent mucin 1 (MUC-1) aptamer on a DNA nanobarrel carrier. We investigated the effect of tail lengths on drug release efficiencies and dual drug codelivery-enabled cytotoxicity. Owing to the rapidly developing field of structural DNA nanotechnology, functional DNA-based drug delivery is promising to achieve clinical therapeutic applications.
Topics: Paclitaxel; Drug Delivery Systems; Antineoplastic Agents; Doxorubicin; Drug Liberation; DNA; Drug Carriers; Cell Line, Tumor; Nanoparticles
PubMed: 37470220
DOI: 10.1002/cbic.202300424 -
International Journal of Oncology Sep 2023Endometrial cancer is the most common gynecologic cancer and one of the only cancers for which incidence and mortality is steadily increasing. Although curable with...
Endometrial cancer is the most common gynecologic cancer and one of the only cancers for which incidence and mortality is steadily increasing. Although curable with surgery in the early stages, endometrial cancer presents a significant clinical challenge in the metastatic and recurrent setting with few novel treatment strategies emerging in the past fifty years. Ipatasertib (IPAT) is an orally bioavailable pan‑AKT inhibitor, which targets all three AKT isoforms and has demonstrated anti‑tumor activity in pre‑clinical models, with clinical trials emerging for many cancer types. In the present study, the MTT assay was employed to evaluate the therapeutic efficacy of IPAT or IPAT in combination with paclitaxel (PTX) in endometrial cancer cell lines and primary cultures of endometrial cancer. The effect of IPAT and PTX on the growth of endometrial tumors was evaluated in a transgenic mouse model of endometrial cancer. Apoptosis was assessed using cleaved caspase assays and cellular stress was assessed using ROS, JC1 and tetramethylrhodamine ethyl ester assays. The protein expression levels of markers of apoptosis and cellular stress, and DNA damage were evaluated using western blotting and immunohistochemistry. IPAT significantly inhibited cell proliferation, caused cell cycle G1 phase arrest, and induced cellular stress and mitochondrial apoptosis in a dose dependent manner in human endometrial cancer cell lines. Combined treatment with low doses of IPAT and PTX led to synergistic inhibition of cell proliferation and induction of cleaved caspase 3 activity in the human endometrial cancer cell lines and the primary cultures. Furthermore, IPAT effectively reduced tumor growth, accompanied by decreased protein expression levels of Ki67 and phosphorylation of S6 in the mouse model of endometrioid endometrial cancer. The combination of IPAT and PTX resulted in increased expression of phosphorylated‑H2AX and KIF14, markers of DNA damage and microtubule dysfunction respectively, as compared with IPAT alone, PTX alone or placebo‑treated mice. The results of the present study provide a biological rationale to evaluate IPAT and the combination of IPAT and PTX in future clinical trials for endometrial cancer.
Topics: Female; Animals; Humans; Mice; Paclitaxel; Proto-Oncogene Proteins c-akt; Piperazines; Cell Proliferation; Endometrial Neoplasms; Apoptosis; Cell Line, Tumor
PubMed: 37503790
DOI: 10.3892/ijo.2023.5551 -
Cancer Medicine Oct 2023Ample evidence reveals that glycolysis is crucial to tumor progression; however, the underlying mechanism of its drug resistance is still worth being further explored....
Ample evidence reveals that glycolysis is crucial to tumor progression; however, the underlying mechanism of its drug resistance is still worth being further explored. TRAF6, an E3 ubiquitin ligase, is well recognized to overexpress in various types of cancer, which predicts a poor prognosis. In our study, we discovered that TRAF6 was expressed more significantly in the case of triple-negative breast cancer (TNBC) than in other of breast cancers, promoting chemoresistance to paclitaxel; that inhibited TRAF6 expression in the chemoresistant TNBC (TNBC-CR) cells enhanced the sensitivity by decreasing glucose uptake and lactate production; that TRAF6 regulated glycolysis and facilitated chemoresistance via binding directly to PKM2; and that overexpressing PKM2 in the TNBC-CR cells with TRAF6 knocked down regained significantly TRAF6-dependent drug resistance and glycolysis. Additionally, we verified that TRAF6 could facilitate PKM2-mediated glycolysis and chemoresistance in animal models and clinical tumor tissues. Thus, we identified the novel function of TRAF6 to promote glycolysis and drug resistance in TNBC with the regulation of PKM2, which could provide a potential molecular target for TNBC treatment.
Topics: Humans; Animals; Triple Negative Breast Neoplasms; Paclitaxel; TNF Receptor-Associated Factor 6; Drug Resistance, Neoplasm; Cell Line, Tumor; Glycolysis; Cell Proliferation; Gene Expression Regulation, Neoplastic
PubMed: 37746908
DOI: 10.1002/cam4.6552 -
ACS Applied Materials & Interfaces Mar 2022Cancer-associated fibroblasts (CAFs), an important type of stromal cells in the tumor microenvironment (TME), are responsible for creating physical barriers to drug...
Sequential Delivery of Quercetin and Paclitaxel for the Fibrotic Tumor Microenvironment Remodeling and Chemotherapy Potentiation via a Dual-Targeting Hybrid Micelle-in-Liposome System.
Cancer-associated fibroblasts (CAFs), an important type of stromal cells in the tumor microenvironment (TME), are responsible for creating physical barriers to drug delivery and penetration in tumor tissues. Thus, effectively downregulating CAFs to destroy the physical barrier may allow enhanced penetration and accumulation of therapeutic drugs, thereby improving therapeutic outcomes. Herein, a matrix metalloproteinase (MMP)-triggered dual-targeting hybrid micelle-in-liposome system (RPM@NLQ) was constructed to sequentially deliver quercetin (Que) and paclitaxel (PTX) for fibrotic TME remodeling and chemotherapy potentiation. Specifically, antifibrotic Que and small-sized RGD-modified micelles containing PTX (RPM) were co-encapsulated into MMP-sensitive liposomes, and the liposomes were further adorned with the NGR peptide (NL) as the targeting moiety. The resulting RPM@NLQ first specifically accumulated at the tumor site under the guidance of the NGR peptide after intravenous administration and then released Que and RPM in response to the extensive expression of MMP in the TME. Subsequently, Que was retained in the stroma to remarkably downregulate fibrosis and decrease the stromal barrier by downregulating Wnt16 expression in CAFs, which further resulted in a significant increase of RPM for deeper tumor. Thus, RPM could precisely target and kill breast cancer cells locally. Consequently, prolonged blood circulation, selective cascade targeting of tumor tissue and tumor cells, enhanced penetration, and excellent antitumor efficacy have been demonstrated in vitro and in vivo. In conclusion, as-designed sequential delivery systems for fibrotic TME remodeling and chemotherapy potentiation may provide a promising adjuvant therapeutic strategy for breast and other CAF-rich tumors.
Topics: Cell Line, Tumor; Drug Delivery Systems; Fibrosis; Humans; Liposomes; Micelles; Paclitaxel; Quercetin; Tumor Microenvironment
PubMed: 35175043
DOI: 10.1021/acsami.1c23166 -
International Journal of Molecular... Mar 2023Epothilone is a natural 16-membered macrolide cytotoxic compound produced by the metabolism of the cellulose-degrading myxobacterium . This review summarizes results in... (Review)
Review
Epothilone is a natural 16-membered macrolide cytotoxic compound produced by the metabolism of the cellulose-degrading myxobacterium . This review summarizes results in the study of epothilones against cancer with preclinical results and clinical studies from 2010-2022. Epothilone have mechanisms of action similar to paclitaxel by inducing tubulin polymerization and apoptosis with low susceptibility to tumor resistance mechanisms. It is active against refractory tumors, being superior to paclitaxel in many respects. Since the discovery of epothilones, several derivatives have been synthesized, and most of them have failed in Phases II and III in clinical trials; however, ixabepilone and utidelone are currently used in clinical practice. There is robust evidence that triple-negative breast cancer (TNBC) treatment improves using ixabepilone plus capecitabine or utidelone in combination with capecitabine. In recent years innovative synthetic strategies resulted in the synthesis of new epothilone derivatives with improved activity against refractory tumors with better activities when compared to ixabepilone or taxol. These compounds together with specific delivery mechanisms could be developed in anti-cancer drugs.
Topics: Humans; Epothilones; Capecitabine; Antineoplastic Agents; Tubulin Modulators; Paclitaxel; Neoplasms
PubMed: 37047035
DOI: 10.3390/ijms24076063 -
Molecules (Basel, Switzerland) Dec 2022Cannabidiol (CBD) is a biologically active compound present in the plants of the family, used as anticonvulsant, anti-inflammatory, anti-anxiety, and more recently,...
Cannabidiol (CBD) is a biologically active compound present in the plants of the family, used as anticonvulsant, anti-inflammatory, anti-anxiety, and more recently, anticancer drug. In this work, its use as a new self-assembly inducer in the formation of nanoparticles is validated. The target conjugates are characterized by the presence of different anticancer drugs (namely -desacetyl thiocolchicine, podophyllotoxin, and paclitaxel) connected to CBD through a linker able to improve drug release. These nanoparticles are formed via solvent displacement method, resulting in monodisperse and stable structures having hydrodynamic diameters ranging from 160 to 400 nm. Their biological activity is evaluated on three human tumor cell lines (MSTO-211H, HT-29, and HepG2), obtaining GI values in the low micromolar range. Further biological assays were carried out on MSTO-211H cells for the most effective NP , confirming the involvement of paclitaxel in cytotoxicity and cell death mechanism.
Topics: Humans; Cannabidiol; Antineoplastic Agents; Paclitaxel; Cell Line, Tumor; Nanoparticles
PubMed: 36615306
DOI: 10.3390/molecules28010112