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Mini Reviews in Medicinal Chemistry 2023Paclitaxel is an anticancer drug first isolated from the bark of the Pacific yew tree. It has been widely used for the treatment of ovarian, breast, uterine and other... (Review)
Review
Paclitaxel is an anticancer drug first isolated from the bark of the Pacific yew tree. It has been widely used for the treatment of ovarian, breast, uterine and other cancers because of its low toxicity, high efficiency and broad-spectrum anticancer activity, and it is considered to be one of the most successful natural anticancer drugs available. Paclitaxel is a microtubule-targeting drug whose main molecular mechanism is to disrupt microtubule dynamics and induce mitotic arrest and cell death. Despite the many clinical successes of paclitaxel, the extraction of natural paclitaxel from Taxus species has proven to be environmentally unsustainable and economically unviable. As a result, researchers are constantly working to find innovative ways to meet society's need for this drug. Currently, many methods, including artificial cultivation, microbial fermentation, chemical synthesis, and tissue and cell culture, have been explored and developed to obtain paclitaxel. In addition, the poor water solubility of paclitaxel has led to significant limitations in its clinical application. Conventional paclitaxel formulations use Cremophor EL and ethanol to dissolve paclitaxel, which can lead to serious side effects. In recent decades, a series of new nanotechnology-based paclitaxel dosage forms have been developed, including albumin-bound paclitaxel, polymeric micellar paclitaxel, polymer-paclitaxel couples, and liposome-encapsulated paclitaxel. These nanoformulations can significantly reduce the toxicity of paclitaxel and greatly improve its anti-tumor efficiency. This paper reviews the development of the production, dosage form and combination therapy of paclitaxel in recent years and presents an outlook, with the aim of providing a theoretical basis and reference for further research on the production and application of paclitaxel in the future.
Topics: Humans; Antineoplastic Agents, Phytogenic; Paclitaxel; Antineoplastic Agents; Drug Delivery Systems; Neoplasms; Polymers
PubMed: 36825714
DOI: 10.2174/1389557523666230210145150 -
Frontiers in Pharmacology 2024Systemic chemotherapy is typically administered following radical gastrectomy for advanced stage. To attenuate systemic side effects, we evaluated the effectiveness of...
Systemic chemotherapy is typically administered following radical gastrectomy for advanced stage. To attenuate systemic side effects, we evaluated the effectiveness of regional chemotherapy using paclitaxel, albumin-paclitaxel, and liposome-encapsulated albumin-paclitaxel via subserosal injection in rat models employing nuclear medicine and molecular imaging technology. Nine Sprague Dawley rats were divided into three groups: paclitaxel ( = 3), albumin-paclitaxel nano-particles (APNs; = 3), and liposome-encapsulated APNs ( = 3). [I]Iodo-paclitaxel ([I]I-paclitaxel) was synthesized by conventional electrophilic radioiodination using -butylstannyl substituted paclitaxel as the precursor. Albumin-[I]iodo-paclitaxel nanoparticles ([I]APNs) were prepared using a desolvation technique. Liposome-encapsulated APNs (L-[I]APNs) were prepared by thin-film hydration using DSPE-PEG2000, HSPC, and cholesterol. The rats in each group were injected with each test drug into the subserosa of the stomach antrum. After predetermined times (30 min, 2, 4, 8 h, and 24 h), molecular images of nuclear medicine were acquired using single-photon emission computed tomography/computed tomography. Paclitaxel, APNs, and L-APNs showed a high cumulative distribution in the stomach, with L-APNs showing the largest area under the curve. Most drugs administered via the gastric subserosal route are distributed in the stomach and intestines, with a low uptake of less than 1% in other major organs. The time to reach the maximum concentration in the intestine for L-APNs, paclitaxel, and APNs was 6.67, 5.33, and 4.00 h, respectively. These preliminary results imply that L-APNs have the potential to serve as a novel paclitaxel preparation method for the regional treatment of gastric cancer.
PubMed: 38904000
DOI: 10.3389/fphar.2024.1381406 -
Pharmaceutics Jul 2023Paclitaxel (PTX) and 5-fluorouracil (5-FU) are clinically relevant chemotherapeutics, but both suffer a range of biopharmaceutical challenges (e.g., either low...
Paclitaxel (PTX) and 5-fluorouracil (5-FU) are clinically relevant chemotherapeutics, but both suffer a range of biopharmaceutical challenges (e.g., either low solubility or permeability and limited controlled release from nanocarriers), which reduces their effectiveness in new medicines. Anticancer drugs have several major limitations, which include non-specificity, wide biological distribution, a short half-life, and systemic toxicity. Here, we investigate the potential of liposome-micelle-hybrid (LMH) carriers (i.e., drug-loaded micelles encapsulated within drug-loaded liposomes) to enhance the co-formulation and delivery of PTX and 5-FU, facilitating new delivery opportunities with enhanced chemotherapeutic performance. We focus on the combination of liposomes and micelles for co-delivery of PTX and 5_FU to investigate increased drug loading, improved solubility, and transport/permeability to enhance chemotherapeutic potential. Furthermore, combination chemotherapy (i.e., containing two or more drugs in a single formulation) may offer improved pharmacological performance. Compared with individual liposome and micelle formulations, the optimized PTX-5FU-LMH carriers demonstrated increased drug loading and solubility, temperature-sensitive release, enhanced permeability in a Caco-2 cell monolayer model, and cancer cell eradication. LMH has significant potential for cancer drug delivery and as a next-generation chemotherapeutic.
PubMed: 37514072
DOI: 10.3390/pharmaceutics15071886 -
Cancer Chemotherapy and Pharmacology Aug 2015To provide the first evaluation of pharmacokinetic (PK) drug-drug interactions (DDIs) between trebananib and chemotherapies across tumor types. (Review)
Review
PURPOSE
To provide the first evaluation of pharmacokinetic (PK) drug-drug interactions (DDIs) between trebananib and chemotherapies across tumor types.
METHODS
PK data of trebananib and chemotherapies (paclitaxel, carboplatin, pegylated liposomal doxorubicin, topotecan, capecitabine, lapatinib, 5-FU, irinotecan, or docetaxel) were collected from trials of ovarian cancer, metastatic breast cancer, colorectal carcinoma, and mixed solid tumor. A dedicated PK DDI study of trebananib and paclitaxel in patients with mixed solid tumors was also conducted. The geometric least squares mean (GLSM) ratios and corresponding 90 % confidence intervals (CI) of C max and AUC were estimated for DDI evaluations.
RESULTS
In the PK DDI study of trebananib and paclitaxel, the GLSM ratio (90 % CI) was 1.17 (1.10-1.25) for paclitaxel AUC and 1.30 (1.15-1.48) for paclitaxel C max. The GLSM ratio (90 % CI) for the effect of paclitaxel on trebananib PK was 0.92 (0.87-0.97) for trebananib AUC and 0.98 (0.92-1.05) for trebananib C max. In the remaining studies, the GLSM ratios (90 % CI) of C max and AUC generally ranged from 0.8 to 1.25 or exhibited less than twofold PK variabilities across chemotherapeutic agents. No dose-dependent DDIs were evident.
CONCLUSIONS
No PK DDI was deemed clinically meaningful between trebananib and the tested chemotherapeutic agents to warrant dose adjustments.
Topics: Antineoplastic Agents; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Drug Interactions; Humans; Paclitaxel; Recombinant Fusion Proteins
PubMed: 26032239
DOI: 10.1007/s00280-015-2748-1 -
International Journal of Pharmaceutics Nov 2022Nanoparticle technology has promising effects on multiple therapeutic purposes, particularly in controlling drug delivery as Drug Delivery System. The unique properties...
Nanoparticle technology has promising effects on multiple therapeutic purposes, particularly in controlling drug delivery as Drug Delivery System. The unique properties of nanoparticles significantly enhance drug delivery, efficiency, and toxicity. For cancer therapy, controlling chemotherapy delivery can increase the drug concentration in the desired locations, improve drug efficacy, and limit drug toxicity. Liposomes are used in this project to encapsulate paclitaxel due to their ability to carry hydrophobic molecules, low toxicity, and prolonged half-life. Among the multiple liposome preparation methods, microfluidic technology was used to produce liposomes. Microfluidics excels in other conventional methods by offering a high-level control of the process's parameters, which help control particle size, size distribution, and physiochemical properties. This project aims to produce paclitaxel-loaded liposomes with a diameter below 200 nm with low polydispersity index, high homogeneity, and good stability. Different lipid types (DMPC, DPPC, DSPC, and DOPC) were used with different ratios to investigate their impact on empty liposome formulation. Alongside changing the different microfluidic parameters including the total flow ratio and flow rate ratio to study their effects on liposomes' physiochemical properties. The obtained formulations were tested to analyse different physiochemical properties (DLS, FTIR) and stability studies. DMPC and DPPC are determined to study their encapsulation efficiency and in vitro drug release of paclitaxel at total flow rate 1 ml min and 1:4 flow rate ratio. The paclitaxel-loaded liposomes are subjected to the same physiochemical characteristics and stability study. Promising encapsulation efficiency was reported from both DPPC and DMPC, and sustained drug release was observed.
Topics: Liposomes; Paclitaxel; Microfluidics; Dimyristoylphosphatidylcholine; Nanoparticles; Particle Size
PubMed: 36272514
DOI: 10.1016/j.ijpharm.2022.122320 -
Wiley Interdisciplinary Reviews.... Mar 2023Chemotherapeutic treatment with conventional drug formulations pose numerous challenges, such as poor solubility, high cytotoxicity and serious off-target side effects,... (Review)
Review
Chemotherapeutic treatment with conventional drug formulations pose numerous challenges, such as poor solubility, high cytotoxicity and serious off-target side effects, low bioavailability, and ultimately subtherapeutic tumoral concentration leading to poor therapeutic outcomes. In the field of Nanomedicine, advances in nanotechnology have been applied with great success to design and develop novel nanoparticle-based formulations for the treatment of various types of cancer. The approval of the first nanomedicine, Doxil® (liposomal doxorubicin) in 1995, paved the path for further development for various types of novel delivery platforms. Several different types of nanoparticles, especially organic (soft) nanoparticles (liposomes, polymeric micelles, and albumin-bound nanoparticles), have been developed and approved for several anticancer drugs. Nanoparticulate drug delivery platform have facilitated to overcome of these challenges and offered key advantages of improved bioavailability, higher intra-tumoral concentration of the drug, reduced toxicity, and improved efficacy. This review introduces various commonly used nanoparticulate systems in biomedical research and their pharmacokinetic (PK) attributes, then focuses on the various physicochemical and physiological factors affecting the in vivo disposition of chemotherapeutic agents encapsulated in nanoparticles in recent years. Further, it provides a review of the current landscape of soft nanoparticulate formulations for the two most widely investigated anticancer drugs, paclitaxel, and doxorubicin, that are either approved or under investigation. Formulation details, PK profiles, and therapeutic outcomes of these novel strategies have been discussed individually and in comparison, to traditional formulations. This article is categorized under: Nanotechnology Approaches to Biology > Cells at the Nanoscale Diagnostic Tools > In Vivo Nanodiagnostics and Imaging Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease.
Topics: Humans; Drug Delivery Systems; Antineoplastic Agents; Liposomes; Doxorubicin; Neoplasms; Nanoparticles
PubMed: 35979879
DOI: 10.1002/wnan.1846 -
Small (Weinheim An Der Bergstrasse,... Oct 2023Immunotherapy gains increasing focus in treating triple-negative breast cancer (TNBC), while its efficacy is greatly restricted owing to low tumor immunogenicity and...
Immunotherapy gains increasing focus in treating triple-negative breast cancer (TNBC), while its efficacy is greatly restricted owing to low tumor immunogenicity and immunosuppressive tumor microenvironment (ITM). Herein, a LyP-1 and chondroitin sulfate (CS) dual-modified liposome co-loaded with paclitaxel (PTX) and cryptotanshinone (CTS), namely CS/LyP-1-PC Lip, is engineered for TNBC chemoimmunotherapy via induction of immunogenic cell death (ICD) and inhibition of signal transducer and activator of transcript-3 (STAT3) activation. CS/LyP-1-PC Lip enhances cellular uptake through p32 and CD44 dual receptor-mediated endocytosis. Within the tumor, the CS layer is continuously detached by hyaluronidase to release drugs. Subsequently, CTS sensitizes the cytotoxicity of PTX to 4T1 tumor cells. PTX induces ICD of tumor cells and facilitates infiltration of cytotoxic T lymphocyte to provoke immune response. Meanwhile, the concomitant delivery of CTS inhibits STAT3 activation to decrease infiltration of regulatory T cell, M2-type tumor-associated macrophage, and myeloid-derived suppressor cell, thus reversing ITM. Markedly, the dual-targeting liposome shows superior anti-tumor efficacy in subcutaneous TNBC mice and significant lung metastasis suppression in tumor metastasis model. Overall, this work offers a feasible combination regimen and a promising nanoplatform for the development of TNBC chemoimmunotherapy.
Topics: Humans; Animals; Mice; Liposomes; Triple Negative Breast Neoplasms; Immunogenic Cell Death; Cell Line, Tumor; Paclitaxel; Immunotherapy; Tumor Microenvironment; STAT3 Transcription Factor
PubMed: 37264710
DOI: 10.1002/smll.202302834 -
International Journal of Biological... Mar 2023Liposomes and nanofibers have been introduced as effective drug delivery systems of anticancer drugs. The performance of chitosan (core)/poly(ε-caprolactone)...
Liposomes and nanofibers have been introduced as effective drug delivery systems of anticancer drugs. The performance of chitosan (core)/poly(ε-caprolactone) (PCL)/paclitaxel simple nanofibers, chitosan/paclitaxel (core)/PCL/chitosan (shell) nanofibers and paclitaxel-loaded liposome-incorporated chitosan (core)/PCL-chitosan (shell) nanofibers was investigated for the controlled release of paclitaxel and the treatment of breast cancer. The synthesized formulations were characterized using polydispersity index, dynamic light scattering, zeta potential, scanning electron microscopy, transmission electron microscopy, and Fourier transform infrared analysis. The sustained release of paclitaxel from liposome-loaded nanofibers was achieved within 30 days. The release data was best described using Korsmeyer-Peppas pharmacokinetic model. The cell viabilities of synthesized nanofibrous samples were higher than 98 % ± 1 % toward L929 normal cells after 168 h. The maximum cytotoxicity against MCF-7 breast cancer cells was 85 % ± 2.5 % using liposome-loaded core-shell nanofibers. The in vivo results indicated the reduction of tumor weight from 1.35 ± 0.15 g to 0.65 ± 0.05 g using liposome-loaded core-shell nanofibers and its increasing from 1.35 ± 0.15 g to 3.2 ± 0.2 g using pure core-shell nanofibers. The three-stage drug release behavior of paclitaxel-loaded liposome-incorporated core-shell nanofibers and the high in vivo tumor efficiency suggested the development of these formulations for cancer treatment in the future.
Topics: Humans; Female; Paclitaxel; Breast Neoplasms; Liposomes; Chitosan; Nanofibers; Polyesters
PubMed: 36706885
DOI: 10.1016/j.ijbiomac.2023.123380 -
Materials Science & Engineering. C,... Aug 2014Nanoengineered drug delivery systems (nDDS) have been successfully used as clinical tools for not only modulation of pharmacological drug release profile but also... (Review)
Review
Nanoengineered drug delivery systems (nDDS) have been successfully used as clinical tools for not only modulation of pharmacological drug release profile but also specific targeting of diseased tissues. Until now, encapsulation of anti-cancer molecules such as paclitaxel, vincristin and doxorubicin has been the main target of nDDS, whereby liposomes and polymer-drug conjugates remained as the most popular group of nDDS used for this purpose. The success reached by these nanocarriers can be imitated by careful selection and optimization of the different factors that affect drug release profile (i.e. type of biomaterial, size, system architecture, and biodegradability mechanisms) along with the selection of an appropriate manufacture technique that does not compromise the desired release profile, while it also offers possibilities to scale up for future industrialization. This review focuses from an engineering perspective on the different parameters that should be considered before and during the design of new nDDS, and the different manufacturing techniques available, in such a way to ensure success in clinical application.
Topics: Antibodies, Monoclonal; Drug Delivery Systems; Humans; Liposomes; Microfluidics; Nanoparticles; Nanotechnology; Pharmaceutical Preparations; Polymers; Serum Albumin
PubMed: 24907751
DOI: 10.1016/j.msec.2014.04.049 -
Breast Cancer Research and Treatment Nov 2020Paclitaxel-based regimens are widely used in the neoadjuvant therapy (NAT) of breast cancer. The purpose is to analysis the efficacy and adverse events (AEs) among...
BACKGROUND AND PURPOSE
Paclitaxel-based regimens are widely used in the neoadjuvant therapy (NAT) of breast cancer. The purpose is to analysis the efficacy and adverse events (AEs) among common paclitaxel (PTX), docetaxel and liposomal paclitaxel. At the same time, we want to analysis the axillary nodal pathologic complete response (apCR) after NAT among the three groups.
METHODS
From April 2014 to 2020, 647 breast cancer patients underwent operation after NAT were included in this study. Patients received full course of anthracycline- and paclitaxel-based chemotherapy before surgery. The paclitaxel-based regimens included PTX, docetaxel and liposomal paclitaxel. The therapy efficacy and AEs of the three groups were evaluated. At the same time, the apCR was also analyzed.
RESULTS
In general, 30.6% (198/647) of patients achieved breast pathologic complete response (bpCR), which was 28.6%, 28.3% and 39.3% among PTX, docetaxel and liposomal paclitaxel group, respectively (p = 0.067). The total pathologic complete response (tpCR) (achieving both bpCR and apCR) was 21.6% (140/647). The tpCR was 13.3%, 19.4% and 34.4% among PTX, docetaxel and liposomal paclitaxel group, respectively (p = 0.026). The multivariate logistic analysis result showed that clinical tumor stage and molecular subtype were significantly associated with tpCR (all p < 0.05). Among 592 clinical positive patients (cN), the apCR was 39.0% (231/592). The multivariate logistic analysis showed that paclitaxel- based regimens and molecular subtype were indicated as independent predictors for apCR of NAT. The apCR was significantly higher in liposomal paclitaxel group (63.5%) than in PTX (24.6%) and docetaxel group (34.8%) (p < 0.001). The subgroup analysis among different molecular subtypes found that in triple negative (TN) and HER-2 positive (HER2+) subgroup, the apCR in liposomal paclitaxel group was significantly higher than those in PTX and docetaxel group (all p < 0.05). But no significant result was found in the subgroup analysis in hormone receptor positive/HER-2 negative subgroup (p = 0.050). Safety analysis indicated that the incidence of neutropenia (grade III-IV) and peripheral neurotoxicity (grade I-II) was significantly lower in the liposomal paclitaxel group than in the PTX and docetaxel group. The incidence of oral mucositis, anaphylaxis and palmar-plantar erythrodysesthesia syndrome was also much lower in liposomal paclitaxel than other two groups (all p < 0.05). And there was no significant difference in other AEs among the three groups (all p > 0.05).
CONCLUSION
Liposome paclitaxel had similar tumor suppressor effect compared with PTX and docetaxel in NAT setting. Moreover, it had a better axillary lymph node (ALN) response after NAT than PTX and docetaxel. These patients who received liposome paclitaxel had more chance to avoid ALN dissection after NAT. At the same time, the application of liposome enables liposome paclitaxel could significantly reduce AEs caused by chemotherapy. Therefore, we suggested the application of liposome paclitaxel in the NAT setting, especially for cN patients with TN and HER2 + disease.
Topics: Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Docetaxel; Female; Humans; Neoadjuvant Therapy; Paclitaxel; Receptor, ErbB-2
PubMed: 32776291
DOI: 10.1007/s10549-020-05851-8