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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 -
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 -
Frontiers in Oncology 2020Paclitaxel liposome (Lipusu) is the first commercialized liposomal formulation of paclitaxel. There has been little data collected on the pharmacokinetics (PK) of...
PURPOSE
Paclitaxel liposome (Lipusu) is the first commercialized liposomal formulation of paclitaxel. There has been little data collected on the pharmacokinetics (PK) of paclitaxel liposome, especially in relation to patient use. This study aimed to build a population pharmacokinetic (PopPK) model and further explore the exposure-safety relationship for paclitaxel liposome in patients with non-small cell lung cancer (NSCLC).
METHODS
Data from 45 patients with a total of 349 plasma concentrations were analyzed. The PopPK model was built using the non-linear mixed effect modeling technique.
RESULTS
The PK of paclitaxel liposome were well described by a three-compartment model with first-order elimination. For a dose of 175 mg m, the estimated clearance of total plasma paclitaxel was 21.55 L h. Age, sex, body weight, total bilirubin, albumin, serum creatinine, and creatinine clearance did not influence the paclitaxel PK. Exposure to paclitaxel had no significant change in the presence of the traditional Chinese medicine, aidi injection. The exploratory exposure-safety relationship was well described by a generalized linear regression model. Higher probabilities of grade >1 neutropenia were observed in patients with higher exposure to paclitaxel.
CONCLUSION
This PopPK model adequately described the PK of paclitaxel liposome in patients with NSCLC. Predicted exposure of paclitaxel did not change in the presence of the traditional Chinese medicine, aidi injection. The exposure-safety analysis suggested that a higher risk of neutropenia was correlated with higher exposure to paclitaxel.
PubMed: 33614470
DOI: 10.3389/fonc.2020.01731 -
AAPS PharmSciTech Feb 2018Paclitaxel (PTX) and gemcitabine (GEM) are often used in combination due to the synergistic anticancer effects. PTX and GEM combination showed a synergistic effect to...
Paclitaxel (PTX) and gemcitabine (GEM) are often used in combination due to the synergistic anticancer effects. PTX and GEM combination showed a synergistic effect to SKOV-3 cells at a molar ratio of 1 to 1 and in PTX ➔ GEM sequence. Liposomes were explored as a carrier of PTX and GEM combination. We optimized the drug loading in liposomes varying the preparation method and co-encapsulated PTX and GEM in a single liposome preparation maintaining the maximum loading efficiency of each drug. However, drug release kinetics from the co-loaded liposomes (LpPG) was suboptimal because of the detrimental effect of PTX on GEM-release control. Instead, a mixture of LpP and LpG, which were separately optimized according to the desired release kinetics, achieved a greater cytotoxic effect than LpPG, due to the attenuation of GEM release relative to PTX. This study illustrates that co-encapsulation in a single carrier is not always desirable for the delivery of drug combinations, when the activity depends on the dosing sequence. These combinations may benefit from the mixed liposome approach, which offers greater flexibility in controlling the ratio and release kinetics of component drugs.
Topics: Cell Line, Tumor; Cell Survival; Deoxycytidine; Dose-Response Relationship, Drug; Drug Delivery Systems; Drug Liberation; Humans; Liposomes; Paclitaxel; Gemcitabine
PubMed: 28971370
DOI: 10.1208/s12249-017-0877-z -
Polymers Feb 2022Paclitaxel (PTX) is a chemotherapeutic agent that belongs to the taxane family and which was approved to treat various kinds of cancers including breast cancer, ovarian... (Review)
Review
Paclitaxel (PTX) is a chemotherapeutic agent that belongs to the taxane family and which was approved to treat various kinds of cancers including breast cancer, ovarian cancer, advanced non-small-cell lung cancer, and acquired immunodeficiency syndrome (AIDS)-related Kaposi's sarcoma. Several delivery systems for PTX have been developed to enhance its solubility and pharmacological properties involving liposomes, nanoparticles, microparticles, micelles, cosolvent methods, and the complexation with cyclodextrins and other materials that are summarized in this article. Specifically, this review discusses deeply the developed paclitaxel nanocrystal formulations. As PTX is a hydrophobic drug with inferior water solubility properties, which are improved a lot by nanocrystal formulation. Based on that, many studies employed nano-crystallization techniques not only to improve the oral delivery of PTX, but IV, intraperitoneal (IP), and local and intertumoral delivery systems were also developed. Additionally, superior and interesting properties of PTX NCs were achieved by performing additional modifications to the NCs, such as stabilization with surfactants and coating with polymers. This review summarizes these delivery systems by shedding light on their route of administration, the methods used in the preparation and modifications, the in vitro or in vivo models used, and the advantages obtained based on the developed formulations.
PubMed: 35215570
DOI: 10.3390/polym14040658 -
Frontiers in Bioengineering and... 2023The incidence and mortality of cancer are gradually increasing. The highly invasive and metastasis of tumor cells increase the difficulty of diagnosis and treatment, so... (Review)
Review
The incidence and mortality of cancer are gradually increasing. The highly invasive and metastasis of tumor cells increase the difficulty of diagnosis and treatment, so people pay more and more attention to the diagnosis and treatment of cancer. Conventional treatment methods, including surgery, radiotherapy and chemotherapy, are difficult to eliminate tumor cells completely. And the emergence of nanotechnology has boosted the efficiency of tumor diagnosis and therapy. Herein, the research progress of nanotechnology used for tumor diagnosis and treatment is reviewed, and the emerging detection technology and the application of nanodrugs in clinic are summarized and prospected. The first part refers to the application of different nanomaterials for imaging and detection , which includes magnetic resonance imaging, fluorescence imaging, photoacoustic imaging and biomarker detection. The distinctive physical and chemical advantages of nanomaterials can improve the detection sensitivity and accuracy to achieve tumor detection in early stage. The second part is about the nanodrug used in clinic for tumor treatment. Nanomaterials have been widely used as drug carriers, including the albumin paclitaxel, liposome drugs, mRNA-LNP, protein nanocages, micelles, membrane nanocomplexes, microspheres et al., which could improve the drug accumulate in tumor tissue through enhanced permeability and retention effect to kill tumor cells with high efficiency. But there are still some challenges to revolutionize traditional tumor diagnosis and anti-drug resistance based on nanotechnology.
PubMed: 37576984
DOI: 10.3389/fbioe.2023.1249875 -
World Journal of Gastroenterology Aug 2016Liposome, albumin and polymer polyethylene glycol are nanovector formulations successfully developed for anti-cancer drug delivery. There are significant differences in... (Review)
Review
Liposome, albumin and polymer polyethylene glycol are nanovector formulations successfully developed for anti-cancer drug delivery. There are significant differences in pharmacokinetics, efficacy and toxicity between pre- and post-nanovector modification. The alteration in clinical pharmacology is instrumental for the future development of nanovector-based anticancer therapeutics. We have reviewed the results of clinical studies and translational research in nanovector-based anti-cancer therapeutics in advanced pancreatic adenocarcinoma, including nanoparticle albumin-bound paclitaxel and nanoliposomal irinotecan. Furthermore, we have appraised the ongoing studies incorporating novel agents with nanomedicines in the treatment of pancreatic adenocarcinoma.
Topics: Adenocarcinoma; Animals; Antineoplastic Agents; CA-19-9 Antigen; Camptothecin; Drug Delivery Systems; Humans; Irinotecan; Liposomes; Nanoparticles; Paclitaxel; Pancreatic Neoplasms
PubMed: 27610018
DOI: 10.3748/wjg.v22.i31.7080 -
Journal of Controlled Release :... Jun 2019Chemotherapy-induced peripheral neuropathy (CIPN) is a major adverse effect of paclitaxel. Several liposome-based products have been approved and demonstrated superior...
Chemotherapy-induced peripheral neuropathy (CIPN) is a major adverse effect of paclitaxel. Several liposome-based products have been approved and demonstrated superior efficacy and safety profiles for other drugs. The first objective of this work was to evaluate the effect of liposome formulation of paclitaxel (L-PTX) on neurotoxicity in-vitro and in-vivo in comparison to the standard Taxol® formulation. The second aim was to investigate the effect of formulation on paclitaxel biodistribution following intravenous administration in an animal model. Free paclitaxel was toxic to cell of neuronal origin (IC50 = 18.4 μg/mL) at a lower concentration than to lung cancer cells (IC50 = 59.1 μg/mL), and L-PTX demonstrated a comparable toxicity in both cell lines (IC50 = 31.8 and 33.7 μg/mL). Administration of L-PTX at 2 mg/kg per dose for a total of 4 doses on day 0, 2, 4, and 6 to rats did not result in increased sensitivity in response to mechanical or thermal stimulation of hind paws, in comparison to Taxol® administration at the same dose level that resulted in neuropathy. Paclitaxel biodisposition was evaluated for two formulations in plasma, liver, lung, brain, spinal cord, skin and muscle of rats after single intravenous dose at 6 mg/kg. The exposure to paclitaxel in brain, spinal cord, muscle, and skin was lower in the L-PTX group compared to Taxol® group. PEGylated liposomes containing paclitaxel were successfully developed and demonstrated reduced neurotoxicity in-vitro in neuronal cells and prevented development of peripheral neuropathy in-vivo. This proof of concept study showed that formulation in nanoparticles is a promising approach for reducing (or preventing) neurotoxicity caused by cancer drugs.
Topics: Animals; Antineoplastic Agents, Phytogenic; Brain; Cell Line, Tumor; Drug Compounding; Humans; Liposomes; Liver; Lung; Male; Muscles; Nanoparticles; Paclitaxel; Peripheral Nervous System Diseases; Rats, Sprague-Dawley; Skin; Spinal Cord; Tissue Distribution
PubMed: 30981814
DOI: 10.1016/j.jconrel.2019.04.013 -
Journal of Food and Drug Analysis Mar 2023The Non-Biological Complex Drug (NBCD) Working Group defines an NBCD as "a medicinal product, not being a biological medicine, where the active substance is not a... (Review)
Review
The Non-Biological Complex Drug (NBCD) Working Group defines an NBCD as "a medicinal product, not being a biological medicine, where the active substance is not a homo-molecular structure, but consists of different (closely related and often nanoparticulate) structures that cannot be isolated and fully quantitated, characterized and/or described by physicochemical analytical means". There are concerns about the potential clinical differences between the follow-on versions and the originator products and within the individual follow-on versions. In the present study, we compare the regulatory requirements for developing generic products of NBCDs in the European Union (EU) and the United States (US). The NBCDs investigated included nanoparticle albumin-bound paclitaxel (nab-paclitaxel) injections, liposomal injections, glatiramer acetate injections, iron carbohydrate complexes, and sevelamer oral dosage forms. The demonstration of pharmaceutical comparability between the generic products and the reference products through comprehensive characterization is emphasized for all product categories investigated. However, the approval pathways and detailed requirements in terms of non-clinical and clinical aspects may differ. The general guidelines in combination with product-specific guidelines are considered effective in conveying regulatory considerations. While regulatory uncertainties still prevail, it is anticipated that through the pilot program established by the European Medicines Agency (EMA) and the FDA, harmonization of the regulatory requirements will be achieved, thereby facilitating the development of follow-on versions of NBCDs.
Topics: Biological Products; Sevelamer
PubMed: 37224550
DOI: 10.38212/2224-6614.3441