RESUMO
Over the past few decades, long acting injectable (LAI) depots of polylactide-co-glycolide (PLGA) or polylactic acid (PLA) based microspheres have been developed for controlled drug delivery to reduce dosing frequency and to improve the therapeutic effects. Biopharmaceuticals such as proteins and peptides are encapsulated in the microspheres to increase their bioavailability and provide a long release period (days or months) with constant drug plasma concentration. The biodegradable and biocompatible properties of PLGA/PLA polymers, including but not limited to molecular weight, end group, lactide to glycolide ratio, and minor manufacturing changes, could greatly affect the quality attributes of microsphere formulations such as release profile, size, encapsulation efficiency, and bioactivity of biopharmaceuticals. Besides, the encapsulated proteins/peptides are susceptible to harsh processing conditions associated with microsphere fabrication methods, including exposure to organic solvent, shear stress, and temperature fluctuations. The protein/peptide containing LAI microspheres in clinical use is typically prepared by double emulsion, coacervation, and spray drying techniques. The purpose of this review is to provide an overview of the formulation attributes and conventional manufacturing techniques of LAI microspheres that are currently in clinical use for protein/peptides. Furthermore, the physicochemical characteristics of the microsphere formulations are deliberated.
Assuntos
Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos , Microesferas , Fragmentos de Peptídeos/administração & dosagem , Poliésteres/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Proteínas/administração & dosagem , Animais , Composição de Medicamentos , Humanos , Fragmentos de Peptídeos/química , Proteínas/químicaRESUMO
Delivery of negatively charged, high molecular weight and unstable siRNA is difficult. The present study describes the development and comparison of cationic liposomes (CLs) and polyamidoamine (PAMAM) dendrimer generation 4 (PG4) nanocarriers of gene for cancer therapy. CLs and PG4 were complexed with anticancer siRNA (siPlk1) to form siPlk1-CLs lipoplex and siPlk1-PG4 dendriplex. siPlk1-CLs/PG4 complexes were characterized for average particle size, zeta potential, fluorescence and integrity of siPlk1 by agarose gel electrophoresis, ethidium bromide intercalation assay, circular dichroism, protection against RNase and stability in serum. The complexation of CLs/siPlk1 and PG4/siPlk1 were at a 100/1 and 2/1 charge ratio respectively. The CLs and PG4 were effective in protecting siPlk1 from RNase activity, also they enhanced the siPlk1 serum stability. Additionally, siPlk1-CLs and siPlk1-PG4 were evaluated by cell culture studies. In vitro anticancer activity study using MCF-7 cells showed that siPlk1-CLs and siPlk1-PG4 causes nearly similar cell death. Both siPlk1-CLs and siPlk1-PG4 resulted in enhanced cellular uptake of siPlk1 in MDA-MB-231 cells compared to naked siPlk1 solution. Cell cycle analysis suggested that increased cell population arrest in subG1 phase by siPlk1-CLs and siPlk1-PG4 compared to naked siPlk1 solution. These observations suggested that CLs and PG4 can be a potential carrier for siPlk1 delivery in breast cancer treatment.
Assuntos
Neoplasias da Mama/tratamento farmacológico , Cátions/química , Proteínas de Ciclo Celular/genética , Dendrímeros/química , Lipossomos/química , Proteínas Serina-Treonina Quinases/genética , Proteínas Proto-Oncogênicas/genética , RNA Interferente Pequeno/administração & dosagem , RNA Interferente Pequeno/genética , Neoplasias da Mama/genética , Ciclo Celular/genética , Linhagem Celular Tumoral , Feminino , Humanos , Células MCF-7 , Tamanho da Partícula , Transfecção/métodos , Quinase 1 Polo-LikeRESUMO
Bone, a fundamental constituent of the human body, is a vital scaffold for support, protection, and locomotion, underscoring its pivotal role in maintaining skeletal integrity and overall functionality. However, factors such as trauma, disease, or aging can compromise bone structure, necessitating effective strategies for regeneration. Traditional approaches often lack biomimetic environments conducive to efficient tissue repair. Nanofibrous microspheres (NFMS) present a promising biomimetic platform for bone regeneration by mimicking the native extracellular matrix architecture. Through optimized fabrication techniques and the incorporation of active biomolecular components, NFMS can precisely replicate the nanostructure and biochemical cues essential for osteogenesis promotion. Furthermore, NFMS exhibit versatile properties, including tunable morphology, mechanical strength, and controlled release kinetics, augmenting their suitability for tailored bone tissue engineering applications. NFMS enhance cell recruitment, attachment, and proliferation, while promoting osteogenic differentiation and mineralization, thereby accelerating bone healing. This review highlights the pivotal role of NFMS in bone tissue engineering, elucidating their design principles and key attributes. By examining recent preclinical applications, we assess their current clinical status and discuss critical considerations for potential clinical translation. This review offers crucial insights for researchers at the intersection of biomaterials and tissue engineering, highlighting developments in this expanding field.
Assuntos
Materiais Biomiméticos , Regeneração Óssea , Microesferas , Nanofibras , Engenharia Tecidual , Humanos , Regeneração Óssea/efeitos dos fármacos , Nanofibras/química , Materiais Biomiméticos/química , Osteogênese/efeitos dos fármacos , Animais , Tamanho da Partícula , Osso e Ossos , Materiais Biocompatíveis/química , Materiais Biocompatíveis/farmacologia , Teste de Materiais , Alicerces Teciduais/químicaRESUMO
Engineered liposomal nanoparticles have unique characteristics as cargo carriers in cancer care and therapeutics. Liposomal theranostics have shown significant progress in preclinical and clinical cancer models in the past few years. Liposomal hybrid systems have not only been approved by the FDA but have also reached the market level. Nanosized liposomes are clinically proven systems for delivering multiple therapeutic as well as imaging agents to the target sites in (i) cancer theranostics of solid tumors, (ii) image-guided therapeutics, and (iii) combination therapeutic applications. The choice of diagnostics and therapeutics can intervene in the theranostics property of the engineered system. However, integrating imaging and therapeutics probes within lipid self-assembly "liposome" may compromise their overall theranostics performance. On the other hand, liposomal systems suffer from their fragile nature, site-selective tumor targeting, specific biodistribution and premature leakage of loaded cargo molecules before reaching the target site. Various engineering approaches, viz., grafting, conjugation, encapsulations, etc., have been investigated to overcome the aforementioned issues. It has been studied that surface-engineered liposomes demonstrate better tumor selectivity and improved therapeutic activity and retention in cells/or solid tumors. It should be noted that several other parameters like reproducibility, stability, smooth circulation, toxicity of vital organs, patient compliance, etc. must be addressed before using liposomal theranostics agents in solid tumors or clinical models. Herein, we have reviewed the importance and challenges of liposomal medicines in targeted cancer theranostics with their preclinical and clinical progress and a translational overview.
Assuntos
Lipossomos , Neoplasias , Humanos , Lipossomos/uso terapêutico , Medicina de Precisão , Reprodutibilidade dos Testes , Distribuição Tecidual , Neoplasias/terapia , Neoplasias/tratamento farmacológico , Fosfolipídeos/uso terapêuticoRESUMO
Triple-negative breast cancer is one of the most lethal cancers. Chemotherapeutics for targeting CDK4 and CDK6 like Palbociclib (PAB) in triple-negative breast cancer was widely explored. However, poor bioavailability and severe side effects profile limiting its clinical usage in the field of cancer chemotherapy. Herein, we set out to develop the stealth liposomes (LPS) of PAB by rotary thin film evaporation with a vesicle size of less than 100 nm. In vitro, drug release studies were performed and fitted into different release kinetic models. LPS were characterized by electron microscopic techniques for morphology. The engineered nanotherapeutics agents were further evaluated in 4T1 triple-negative breast cancer cell lines for its anti-cancer potential and cellular uptake. The hemolytic potential and pharmacokinetic (PK) behavior of developed LPS-PAB and PAB were analyzed by using robust UHPLC-QTOF-MS method. LPS-PAB demonstrates biphasic release profile with first-order release kinetics. Further, LPS-PAB has shown less IC50 value (1.99 µM) compared to PAB alone (3.24 µM). The designed nanoliposomes were tagged with fluorescent FITC dye to check rapid cellular uptake. Importantly, stealth LPS-PAB has shown a 1.75-fold reduction in hemolytic potential as compared to PAB plain drug at 100 µg/mL concentration. The PK results obtained was displayed 2.5-fold increase in Cmax, 1.45-fold increase in AUCtot, 1.8-fold increase in half-life and 1.3-fold increase in MRT with LPS-PAB when compared to orally administered PAB suspension. These findings suggest that novel LPS-PAB can be employed as an alternate therapeutic strategy to eradicate triple-negative breast cancer.
Assuntos
Antineoplásicos , Neoplasias de Mama Triplo Negativas , Antineoplásicos/uso terapêutico , Liberação Controlada de Fármacos , Humanos , Lipopolissacarídeos/uso terapêutico , Lipossomos , Neoplasias de Mama Triplo Negativas/tratamento farmacológicoRESUMO
Liposomes have several advantages, such as the ability to be employed as a carrier/vehicle for a variety of drug molecules and at the same time they are safe and biodegradable. In the recent times, compared to other delivery systems, liposomes have been one of the most well-established and commercializing drug products of new drug delivery methods for majority of therapeutic applications. On the other hand, it has several limitations, particularly in terms of stability, which impedes product development and performance. In this review, we reviewed all the potential instabilities (physical, chemical, and biological) that a formulation development scientist confronts throughout the development of liposomal formulations as along with the ways to overcome these challenges. We have also discussed the effect of microbiological contamination on liposomal formulations with a focus on the use of sterilization methods used to improve the stability. Finally, we have reviewed quality control techniques and regulatory considerations recommended by the agencies (USFDA and MHLW) for liposome drug product development.
Assuntos
Sistemas de Liberação de Medicamentos , Lipossomos , Desenvolvimento de Medicamentos , Excipientes , Lipossomos/química , Controle de QualidadeRESUMO
Exosomes are endogenous extracellular vesicles (30-100 nm) composed with membrane lipid bilayer which carry vesicular proteins, enzymes, mRNA, miRNA and nucleic acids. They act as messengers for intra- and inter-cellular communication. In addition to their physiological roles, exosomes have the potential to encapsulate and deliver small chemotherapeutic drugs and biological molecules such as proteins and nucleic acid-based drugs to the recipient tissue or organs. Due to their biological properties, exosomes have better organotropism, homing capacity, cellular uptake and cargo release ability than other synthetic nano-drug carriers such as liposomes, micelles and nanogels. The secretion of tumor-derived exosomes is increased in the hypoxic and acidic tumor microenvironment, which can be used as a target for nontoxic and nonimmunogenic drug delivery vehicles for various cancers. Moreover, exosomes have the potential to carry both hydrophilic and hydrophobic chemotherapeutic drugs, bypass RES effect and bypass BBB. Exosomes can be isolated from other types of EVs and cell debris based on their size, density and specific surface proteins through ultracentrifugation, density gradient separation, precipitation, immunoaffinity interaction and gel filtration. Drugs can be loaded into exosomes at the biogenesis stage or with the isolated exosomes by incubation, electroporation, extrusion or sonication methods. Finally, exosomal cargo vehicles can be characterized by ultrastructural microscopic analysis. In this review we intend to summarize the inception, structure and function of the exosomes, role of exosomes in immunological regulation and cancer, methods of isolation and characterization of exosomes and products under clinical trials. This review will provide an inclusive insight of exosomes in drug delivery.
Assuntos
Exossomos , Vesículas Extracelulares , Lipossomos , Proteínas de Membrana , Microambiente TumoralRESUMO
Lignin is an abundant renewable natural biopolymer. Moreover, a significant development in lignin pretreatment and processing technologies has opened a new window to explore lignin and lignin-based bionanomaterials. In the last decade, lignin has been widely explored in different applications such as drug and gene delivery, tissue engineering, food science, water purification, biofuels, environmental, pharmaceuticals, nutraceutical, catalysis, and other interesting low-value-added energy applications. The complex nature and antioxidant, antimicrobial, and biocompatibility of lignin attracted its use in various biomedical applications because of ease of functionalization, availability of diverse functional sites, tunable physicochemical and mechanical properties. In addition to it, its diverse properties such as reactivity towards oxygen radical, metal chelation, renewable nature, biodegradability, favorable interaction with cells, nature to mimic the extracellular environment, and ease of nanoparticles preparation make it a very interesting material for biomedical use. Tremendous progress has been made in drug delivery and tissue engineering in recent years. However, still, it remains challenging to identify an ideal and compatible nanomaterial for biomedical applications. In this review, recent progress of lignin towards biomedical applications especially in drug delivery and in tissue engineering along with challenges, future possibilities have been comprehensively reviewed.
Assuntos
Sistemas de Liberação de Medicamentos , Técnicas de Transferência de Genes , Lignina/química , Engenharia Tecidual , Animais , Biomassa , Humanos , Nanopartículas/química , Nanopartículas/ultraestruturaRESUMO
Amorphous solid dispersions (ASDs) are being employed frequently to improve bioavailability of poorly soluble molecules by enhancing the rate and extant of dissolution in drug product development process. These systems comprise of an amorphous active pharmaceutical ingredient stabilized by a polymer matrix to provide enhanced stability. This review discussed the methodologies of preparation and characterization of ASDs with an emphasis on understanding and predicting stability. Rational selection of polymers, preparation techniques with its advantages and disadvantages and characterization of polymeric amorphous solid dispersions have discussed. Stability aspects have been described as per ICH guidelines which intend to depend on selection of polymers and preparation methods of ASD. The mechanism involved on improvement of bioavailability also considered. Regulatory importance of ASD and current evolving details of QBD approach were reviewed. Amorphous products and particularly ASDs are currently most emerging area in the pharmaceutical field. This strategic approach presents huge impact and advantageous features concerning the overall improvement of drug product performance in clinical settings which ultimately lead to drug product approval by leading regulatory agencies into the market.
Assuntos
Química Farmacêutica , Preparações Farmacêuticas/administração & dosagem , Polímeros/química , Animais , Disponibilidade Biológica , Composição de Medicamentos , Estabilidade de Medicamentos , Humanos , Preparações Farmacêuticas/química , Preparações Farmacêuticas/metabolismo , SolubilidadeRESUMO
Cancer stem cells (CSCs) are the promising targets for cancer chemotherapy that cannot be eliminated by conventional chemotherapy. In this study cationic liposomes of cabazitaxel (CBX) and silibinin (SIL) were prepared with an aim to kill cancer cells and CSCs for prostate cancer. CBX act as cancer cell inhibitor and SIL as CSC inhibitor. Hyaluronic acid (HA), an endogenous anionic polysaccharide was coated on cationic liposomes for targeting CD44 receptors over expressed on CSCs. Liposomes were prepared by ethanol injection method with particle size below 100 nm and entrapment efficiency of more than 90% at 10% w/w drug loading. Liposomes were characterized by dynamic light scattering, transmission electron microscopy, 1H nuclear magnetic resonance and scanning electron microscopy-energy dispersive x-ray spectroscopy. Liposomes were evaluated for their anticancer action in androgen independent human prostate cancer cell lines (PC-3 and DU-145). HA coated liposomes showed potential cytotoxicity over other groups with low IC50, significantly inhibited cell migration and induced apoptosis. Synergistic cytotoxic effect was also observed with HA coated liposomes that resulted in colony formation inhibition and G2/M phase arrest. Proficient cytotoxicity against CD44+ cells (14.87 ± 0.41% in PC-3 and 33.95 ± 0.68% in DU-145 cells) indicated the efficiency of HA coated liposomes towards CSC targeting. Hence, the outcome of this combinational therapy with CD44 targeting indicates the suitability of HA coated CBX and SIL co-loaded liposomes as a potential approach for eradicating prostate cancer and herein might provide a insight for future studies.
Assuntos
Sistemas de Liberação de Medicamentos/métodos , Receptores de Hialuronatos/administração & dosagem , Nanomedicina/métodos , Neoplasias da Próstata , Silibina/administração & dosagem , Taxoides/administração & dosagem , Antineoplásicos Fitogênicos/administração & dosagem , Antineoplásicos Fitogênicos/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Cátions , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Humanos , Receptores de Hialuronatos/metabolismo , Lipossomos , Masculino , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/metabolismo , Silibina/farmacocinética , Taxoides/farmacocinética , Ensaio Tumoral de Célula-Tronco/métodosRESUMO
Cabazitaxel as microtubule inhibitor and thymoquinone as HDAC inhibitor affects the important genes like p53, STAT3, Bax, BCL-2, p21 and down regulation of NF-κB are reported for potential activity against breast tumors. However, poor aqueous solubility and permeability hinders the delivery of these drugs to target site. To address the delivery challenges cabazitaxel and thymoquinone co-loaded lipospheres were developed. Lipospheres are the lipid based self-assemblies of particle size below 150 nm were prepared with more than 90% entrapment efficiency for both the drugs. In vitro drug release studies revealed there was a sustained diffusion controlled drug release from liposphere matrix leading to decrease in particle size with increase in zeta potential. Cytotoxicity studies on MCF-7 and MDA-MB-231 cells demonstrated cabazitaxel and thymoquinone as synergistic combination for the treatment of breast cancer which was proved by CompuSyn software. Enhanced efficacy of developed lipospheres can be due to rapid cellular internalization which was observed in confocal laser scanning microscopy. Drastic changes in cancer cell morphology such as nuclear fragmentation were observed upon treatment with these lipospheres in comparison to combination solution as observed in fluorescent imaging which are the hall marks of apoptosis. Cell cycle analysis and apoptosis studies confirmed the increased Sub G1 phase arrest as well as cell death due to apoptosis. Thus, as per observed results, it can be concluded that cabazitaxel and thymoquinone co-loaded lipospheres are the efficient delivery vehicles in management of breast cancer.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/química , Benzoquinonas/química , Neoplasias da Mama/tratamento farmacológico , Lipídeos/química , Lipossomos/química , Taxoides/química , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Apoptose/efeitos dos fármacos , Benzoquinonas/farmacologia , Linhagem Celular Tumoral , Permeabilidade da Membrana Celular , Composição de Medicamentos/métodos , Liberação Controlada de Fármacos , Feminino , Humanos , Imagem Óptica , Solubilidade , Taxoides/farmacologiaRESUMO
Topical delivery of siRNA is challenging task due to complex barrier property of stratum corneum and cationic lipid based carriers have been widely explored for this purpose due to improved permeation through skin. For gene delivery application, dendrimers are considered as efficient carrier due to their cationic nature and well-defined surface groups. However, they are not well explored for topical delivery. This work compares the suitability of PAMAM dendrimer with DOTAP liposome for topical delivery of siRNA against TNF-α. The particle size, zeta potential and entrapment efficiency of dendriplex were 99.80⯱â¯1.80â¯nm, 13.40⯱â¯4.84â¯mV and 98.72⯱â¯2.02% whereas for lipoplex were 174.80⯱â¯0.80â¯nm, 29.96⯱â¯0.51â¯mV and 94.99⯱â¯5.01% respectively. Both the formulations were stable in serum and in the presence of RNAse. TNF-α is inflammatory cytokine, hence the in vivo efficacy of developed formulations was determined using psoriatic plaque model. Results suggested improved phenotypic and histopathological features and reduced levels of IL-6, TNF-α, IL-17 and IL-22 for dendriplex and lipoplex treated groups in comparison to Imiquimod treated group. These findings suggest that dendrimer can be a potential carrier for topical gene delivery.