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Cancer stem cells and strategies for targeted drug delivery
Jin Cao, Shubhmita Bhatnagar, Jiawei Wang, Xueyong Qi, Swayam Prabha & Jayanth Panyam
doi : 10.1007/s13346-020-00863-9
Drug Delivery and Translational Research volume 11, pages1779–1805 (2021)
Cancer stem cells (CSCs) are a small proportion of cancer cells with high tumorigenic activity, self-renewal ability, and multilineage differentiation potential. Standard anti-tumor therapies including conventional chemotherapy, radiation therapy, and molecularly targeted therapies are not effective against CSCs, and often lead to enrichment of CSCs that can result in tumor relapse. Therefore, it is hypothesized that targeting CSCs is key to increasing the efficacy of cancer therapies. In this review, CSC properties including CSC markers, their role in tumor growth, invasiveness, metastasis, and drug resistance, as well as CSC microenvironment are discussed. Further, CSC-targeted strategies including the use of targeted drug delivery systems are examined.
Local administration of submicron particle paclitaxel to solid carcinomas induces direct cytotoxicity and immune-mediated tumoricidal effects without local or systemic toxicity: preclinical and clinical studies
Shelagh Verco, Holly Maulhardt, Michael Baltezor, Emily Williams, Marc Iacobucci, Alison Wendt, James Verco, Alyson Marin, Sam Campbell, Paul Dorman & Gere diZerega
doi : 10.1007/s13346-020-00868-4
Drug Delivery and Translational Research volume 11, pages1806–1817 (2021)
This report describes local administration of submicron particle paclitaxel (SPP) (NanoPac®: ~ 800-nm-sized particles with high relative surface area with each particle containing?~ 2 billion molecules of paclitaxel) in preclinical models and clinical trials evaluating treatment of carcinomas. Paclitaxel is active in the treatment of epithelial solid tumors including ovarian, peritoneal, pancreatic, breast, esophageal, prostate, and non-small cell lung cancer. SPP has been delivered directly to solid tumors, where the particles are retained and continuously release the drug, exposing primary tumors to high, therapeutic levels of paclitaxel for several weeks. As a result, tumor cell death shifts from primarily apoptosis to both apoptosis and necroptosis. Direct local tumoricidal effects of paclitaxel, as well as stimulation of innate and adaptive immune responses, contribute to antineoplastic effects. Local administration of SPP may facilitate tumor response to systemically administered chemotherapy, targeted therapy, or immunotherapy without contributing to systemic toxicity. Results of preclinical and clinical investigations described here suggest that local administration of SPP achieves clinical benefit with negligible toxicity and may complement standard treatments for metastatic disease.
Single domain antibody-based vectors in the delivery of biologics across the blood–brain barrier: a review
Yang Gao, Jianwei Zhu & Huili Lu
doi : 10.1007/s13346-020-00873-7
Drug Delivery and Translational Research volume 11, pages1818–1828 (2021)
Biologics are a promising and effective method for the treatment of central nervous system (CNS) diseases. The blood–brain barrier (BBB) is a natural barrier for the delivery of biologics into the brain, which decreases the effective concentration of drugs in the CNS. A range of strategies has been explored to transport biologics across the BBB endothelium, typically via receptor-mediated transcytosis (RMT), which involving molecules for endogenous BBB receptors to be fused with biologics. This review emphasized a category of novel alternative RMT-targeting vectors: single domain antibodies (sdAb). SdAbs are a unique category of antibodies derived from naturally occurring heavy-chain-only antibodies. Herein, we describe their properties, mechanisms, modifications, and translational perspectives for their ability to transmigrate across the BBB in vitro and in vivo in detail.
Repurposing drug molecules for new pulmonary therapeutic interventions
Piyush P. Mehta & Vividha S. Dhapte-Pawar
doi : 10.1007/s13346-020-00874-6
Drug Delivery and Translational Research volume 11, pages1829–1848 (2021)
Drug repurposing with novel strategies has substantially contributed to the identification and analysis of new molecules for better pulmonary intervention. This review would offer insights into the drug repurposing for effective pulmonary therapy. The review begins by explaining the relevant background knowledge of drug repurposing, the need for drug repurposing, and their potential advantages in treating pulmonary diseases. This article takes into account clinical trial problems, drug delivery challenges, regulatory issues, and human ergonomics along with chemistry manufacturing and control strategies for effective pulmonary drug repurposing. This article elaborates on pulmonary drug repurposing with help of strengths, weaknesses, opportunities, and threat analysis. In brief, this article is the first inclusive account of drug repurposing for better pulmonary therapy.
Gastro-retentive drug delivery systems: a recent update on clinical pertinence and drug delivery
Supratim Das, Sukhbir Kaur & Vineet Kumar Rai
doi : 10.1007/s13346-020-00875-5
Drug Delivery and Translational Research volume 11, pages1849–1877 (2021)
Gastro-retentive drug delivery systems are some of the best technologies delivered through oral route. These mainly came into picture for their effective local action in the GI region, specifically for the drugs with narrow absorption window. In the recent decades, several technologies have evolved showing different mechanisms for retaining the drug in GI region for longer duration with increased bioavailability. Floatable, mucoadhesive, swelable, magnetic, nanofibrous, high-density, and expandable systems have been investigated extensively as the potential gastro-retentive strategies. The advances in the technologies studied, their clinical pertinence, and methods of drug delivery are described in this review with their immense future utilities. Their entry into the pharmaceutical market is a huge matter to look into as most of the studied strategies are facing problems and hence are underrated to overcome the clinical trials. Their success in the clinical trials are enormously required for gaining their access into the pharmaceutical market. Selection of the right technology for the right purpose through the right mechanism of action is to be done for obtaining the system with desired activity.
Intelligent automated drug administration and therapy: future of healthcare
Richa Sharma, Dhirendra Singh, Prerna Gaur & Deepak Joshi
doi : 10.1007/s13346-020-00876-4
Drug Delivery and Translational Research volume 11, pages1878–1902 (2021)
In the twenty-first century, the collaboration of control engineering and the healthcare sector has matured to some extent; however, the future will have promising opportunities, vast applications, and some challenges. Due to advancements in processing speed, the closed-loop administration of drugs has gained popularity for critically ill patients in intensive care units and routine life such as personalized drug delivery or implantable therapeutic devices. For developing a closed-loop drug delivery system, the control system works with a group of technologies like sensors, micromachining, wireless technologies, and pharmaceuticals. Recently, the integration of artificial intelligence techniques such as fuzzy logic, neural network, and reinforcement learning with the closed-loop drug delivery systems has brought their applications closer to fully intelligent automatic healthcare systems. This review’s main objectives are to discuss the current developments, possibilities, and future visions in closed-loop drug delivery systems, for providing treatment to patients suffering from chronic diseases. It summarizes the present insight of closed-loop drug delivery/therapy for diabetes, gastrointestinal tract disease, cancer, anesthesia administration, cardiac ailments, and neurological disorders, from a perspective to show the research in the area of control theory.
Fouling in ocular devices: implications for drug delivery, bioactive surface immobilization, and biomaterial design
Onyinye J. Uwaezuoke, Pradeep Kumar, Viness Pillay & Yahya E. Choonara
doi : 10.1007/s13346-020-00879-1
Drug Delivery and Translational Research volume 11, pages1903–1923 (2021)
The last 30 years has seen a proliferation of research on protein-resistant biomaterials targeted at designing bio-inert surfaces, which are prerequisite for optimal performance of implantable devices that contact biological fluids and tissues. These efforts have only been able to yield minimal results, and hence, the ideal anti-fouling biomaterial has remained elusive. Some studies have yielded biomaterials with a reduced fouling index among which high molecular weight polyethylene glycols have remained dominant. Interestingly, the field of implantable ocular devices has not experienced an outflow of research in this area, possibly due to the assumption that biomaterials tested in other body fluids can be translated for application in the ocular space. Unfortunately, progression in the molecular understanding of many ocular conditions has brought to the fore the need for treatment options that necessitates the use of anti-fouling biomaterials. From the earliest implanted horsehair and silk seton for glaucoma drainage to the recent mini telescopes for sight recovery, this review provides a concise incursion into the gradual evolution of biomaterials for the design of implantable ocular devices as well as approaches used to overcome the challenges with fouling. The implication of fouling for drug delivery, the design of immune-responsive biomaterials, as well as advanced surface immobilization approaches to support the overall performance of implantable ocular devices are also reviewed.
Towards the use of localised delivery strategies to counteract cancer therapy–induced cardiotoxicities
David S. Monahan, Talal Almas, Robert Wyile, Faisal H. Cheema, Garry P. Duffy & Aamir Hameed
doi : 10.1007/s13346-020-00885-3
Drug Delivery and Translational Research volume 11, pages1924–1942 (2021)
Cancer therapies have significantly improved cancer survival; however, these therapies can often result in undesired side effects to off target organs. Cardiac disease ranging from mild hypertension to heart failure can occur as a result of cancer therapies. This can warrant the discontinuation of cancer treatment in patients which can be detrimental, especially when the treatment is effective. There is an urgent need to mitigate cardiac disease that occurs as a result of cancer therapy. Delivery strategies such as the use of nanoparticles, hydrogels, and medical devices can be used to localise the treatment to the tumour and prevent off target side effects. This review summarises the advancements in localised delivery of anti-cancer therapies to tumours. It also examines the localised delivery of cardioprotectants to the heart for patients with systemic disease such as leukaemia where localised tumour delivery might not be an option.
Promising bioadhesive ofloxacin-loaded polymeric nanoparticles for the treatment of ocular inflammation: formulation and in vivo evaluation
Alaa H. Salama, Mona M. AbouSamra, Ghada E. A. Awad & Soheir S. Mansy
doi : 10.1007/s13346-020-00856-8
Drug Delivery and Translational Research volume 11, pages1943–1957 (2021)
Our work tackles the combined advantages of both nanotechnology and the bioadhesive gel properties which were utilized to design an ocular drug delivery system that is capable to treat ocular inflammation. Nanoparticles encapsulating an antibiotic drug, ofloxacin, were fabricated using emulsion solvent evaporation technique adopting 23 full factorial design to evaluate the effect of formulation parameters: that is to say, the molecular weight of the polymer (polycaprolactone), amount of Kolliphor P188, and presence of the charge inducer (chitosan hydrochloride) on the measured responses: drug entrapment efficiency (EE%), particle size (PS), polydispersity index (PDI) and zeta potential (ZP). The results show that the optimized LPCL-NP2 formulation (composed of low molecular weight polycaprolactone, 500 mg of Kolliphor P188, 0.25% chitosan hydrochloride, and 50 mg ofloxacin) displayed a sphere shape with EE%, PS, PDI, and ZP values of 89.73?±?0.04%, 195.4?±?13.17 nm, 0.323?±?0.01, and 55.4?±?0.66 mV, respectively. DSC study confirmed the amorphous nature of the drug. The optimized nanoparticle formulation was then further incorporated into the following two ocular formulations: gel (LPCL-NP2-G4) and in situ forming gel (LPCL-NP2-ISG4). The penetration of optimized ocular formulations was assessed by confocal laser scanning microscopy. The antimicrobial study was conducted for the following three ocular formulations: LPCL-NP2 presented as eye drops, LPCL-NP2-G4, and LPCL-NP2-ISG4 as well as the market product using rabbits which were infected in their eyes with Escherichia coli. Results revealed that rabbits treated with LPCL-NP2-ISG4 demonstrated a remarkable antibacterial efficacy and evident low bacterial growth which was additionally assured by the histopathological examination of eye biopsies compared with the other investigated groups. Thus, a novel ofloxacin-loaded nanoparticle formulation based on polycaprolactone is presented in the form of mucoadhesive non-irritating in situ forming ocular gel possessing a superior antibacterial activity.
A dry powder inhalable formulation of salvianolic acids for the treatment of pulmonary fibrosis: safety, lung deposition, and pharmacokinetic study
Linxia Jiang, Yijun Li, Jiaqi Yu, Jianhong Wang, Jiarui Ju & Jundong Dai
doi : 10.1007/s13346-020-00857-7
Drug Delivery and Translational Research volume 11, pages1958–1968 (2021)
Salvianolic acids (SAL), the main bioactive component extracted from Salvia miltiorrhiza, is a natural product with a reported anti-pulmonary fibrosis (PF) effect. SAL is commonly administrated orally; however, it has a low oral bioavailability (less than 5%). The objective of this work was to develop a new dry powder inhalable formulation intended to facilitate the access of SAL to the target place. We prepared the new SAL powder formulation containing L-arginine and 2% of lecithin using the ball milling technique. L-arginine was used to regulate the strong acidity of the SAL solution, and lecithin was added to disperse the powder and improve the flowability. The resulting powder had a content in salvianolic acid B (SALB, the main active principle of SAL) of 66.67%, a particle size of less than 5 ?m and a good flowability. In vivo fluorescence imaging showed that the powder could be successfully aerosolized and delivered to the lung. The acute lung irritation study proved that the presence of L-arginine improved the biocompatibility of the powder. Finally, according to the pharmacokinetic study, the new SAL powder formulation was found to significantly increase drug concentration in the lung and the bioavailability. In conclusion, the new dry powder inhalable formulation of SAL developed in this study could be a strategy to enhance the performance of SAL at the lung level.
A multicomponent-based microemulsion for boosting ovarian cancer therapy through dual modification with transferrin and SA-R6H4
Haijun Zhao, Mengyuan Chen, Zhujiang Zhao, Linjia Zhu & Shaofei Yuan
doi : 10.1007/s13346-020-00859-5
Drug Delivery and Translational Research volume 11, pages1969–1982 (2021)
Balancing the antitumor activity and systemic toxicity of tripterine still faces a big challenge due to the narrow therapeutic window. To address this issue, we report a microemulsion system based on tripterine, brucea oil, and glycyrrhizin, and dual modified with both transferrin and cell-penetrating peptide SA-R6H4 (Tf/SA-R6H4-TBG-MEs) for combinational and tumor-targeted cancer therapy. Such a microemulsion exhibited a spherical shape with a size of ~50 nm and a mildly-negative charge. The half-maximal inhibitory concentration (IC50) of Tf/SA-R6H4-TBG-MEs against ovarian cancer SKOV3 cells was 0.27 ± 0.43 ?g tripterine/mL, which was 5.85 times lower than that of free tripterine. The cellular uptake of tripterine after treatment with Tf/SA-R6H4-TBG-MEs was 1.56 times higher than that of TBG-MEs (non-modified microemulsion). In pharmacokinetics studies, the area under the curve of Tf/SA-R6H4-TBG-MEs increased by 1.97 times compared with that of the physical mixture group. The tumoral accumulation of tripterine was significantly improved in Tf/SA-R6H4-TBG-MEs group than TBG-MEs-treated group. In antitumor efficacy in vivo, Tf/SA-R6H4-TBG-MEs exhibited the strongest inhibition of tumor growth and the longest survival period among all the groups, which is associated with the rational combination, microemulsion system, and dual modification with tumor-targeted ligands. Importantly, Tf/SA-R6H4-TBG-MEs significantly reduced the toxicity of tripterine against the liver and kidney. Our design provides a new approach for efficient and safe ovarian cancer therapy based on a multicomponent combination.
Improving sciatic nerve regeneration by using alginate/chitosan hydrogel containing berberine
Majid Rahmati, Arian Ehterami, Reza Saberani, Ghasem Abbaszadeh-Goudarzi, Nariman Rezaei Kolarijani, Hossein Khastar, Behzad Garmabi & Majid Salehi
doi : 10.1007/s13346-020-00860-y
Drug Delivery and Translational Research volume 11, pages1983–1993 (2021)
Peripheral nerve injuries are the common results of trauma that lead to pain and handicap in patients. Berberine due to its properties like antibiotic, immunostimulant, antitumor, antimotility, and positive effect on neurological disorders can be used to enhance peripheral nerve injuries. In this study, alginate/chitosan hydrogel containing different concentrations of berberine (0, 0.1, 1, 10% (w/v)) was created, evaluated, and applied as a scaffold for sciatic nerve regeneration. To prepare hydrogel, sodium alginate was dissolved in distilled water and cross-linked with CaCl2, and chitosan was dissolved in acetic acid and cross-linked with ?-glycerol phosphate. The structure, release, swelling, weight loss, cytocompatibility, and hemocompatibility of the prepared hydrogels were assessed. The sciatic nerve crush was created in rats and fabricated hydrogels were injected, and functional analysis was used to evaluate their effectiveness. The results of physical characterization of the hydrogel indicated that the initial average pore size was about 39 ?m and about 70% of the main weight of hydrogels was lost after incubation for 21 days and hemocompatibility of hydrogels was also confirmed. The MTT assay showed the cytocompatiblity of hydrogels and also indicated that berberine has dose-dependence effect on cell proliferation. The in vivo results showed the positive effect of berberine especially the hydrogel contained 1% of berberine on regeneration of sciatic nerve. Based on this study, Alg/Chit hydrogel can be applied as a treatment to heal peripheral nerve injuries.
Chondroitin sulfate conjugation facilitates tumor cell internalization of albumin nanoparticles for brain-targeted delivery of temozolomide via CD44 receptor-mediated targeting
Ritu R. Kudarha & Krutika K. Sawant
doi : 10.1007/s13346-020-00861-x
Drug Delivery and Translational Research volume 11, pages1994–2008 (2021)
In the present investigation, temozolomide (TMZ) loaded chondroitin sulfate conjugated albumin nanoparticles (CS-TNPs) were fabricated by desolvation method were chondroitin sulfate (CS) was used as the surface exposed ligand to achieve CD44 receptor mediated targeting of brain tumor. The developed CS-TNPs were characterized for particle size, zeta potential, entrapment efficiency and drug loading and evaluated by FTIR, DSC, XRD and TEM analysis. BBB (blood brain barrier) passage study using in vitro BBB model indicated that CS-TNPs were able to efficiently cross the BBB. Cell viability assay data demonstrated higher cytotoxicity of CS-TNPs as compared with pure TMZ. The CD44 receptor blocking assay and receptor poisoning assay in U87 MG cells confirmed the CD44 receptor and endocytosis-mediated (caveolae pathway) uptake of CS-TNPs. CS-TNPs were able to generate ROS in U87 MG cells. In vivo pharmacokinetic and biodistribution studies were performed in Wistar rats. In vivo results revealed significant enhancement in pharmacokinetic profile of CS-TNPs as compared with TMZ alone. Biodistribution results demonstrated higher accumulation of TMZ in the brain by CS-TNPs as compared with the pure drug that confirmed the brain targeting ability of nanoparticles. From all obtained results, it may be concluded that CS-TNPs are promising carrier to deliver TMZ to the brain for targeted therapy of brain tumor.
Formulation and optimization of microsponge-loaded emulgel to improve the transdermal application of acyclovir—a DOE based approach
Tejal Gusai, Mori Dhavalkumar, Moinuddin Soniwala, Kiran Dudhat, Jaydip Vasoya & Jayant Chavda
doi : 10.1007/s13346-020-00862-w
Drug Delivery and Translational Research volume 11, pages2009–2029 (2021)
The cutaneous penetration of acyclovir from the conventional topical formulations such as cream and ointments is poor due to low water solubility and low octanol buffer partition coefficient of the drug. The present investigation was aimed to prepare acyclovir-loaded microsponge-based emulgel to improve its topical delivery. The microsponges were prepared by the quasi-emulsion diffusion method. The central composite design was employed to investigate the effect of changes in various formulation and process parameters on critical product attributes. Homogenization speed (X1), drug/polymer ratio (X2), and concentration of PVA (X3) were selected as independent variables while particle size,b% yield, % drug loading efficiency, % entrapment efficiency, the drug released at 0.25 h and 6 h were selected as response variables. The regression analysis proved a significant effect of all the independent variables on the dependent variables (p < 0.05). All the designed batches released more than 40% drug in less than 1 h and were also able to sustain the drug release for more than 6 h. Based on the solution suggested by the software, the optimized batch was prepared with 1000-rpm homogenization speed, 1.6:1 drug/polymer ratio, and 0.088% of PVA. The optimized microsponge-loaded emulgel had acceptable viscosity (10,897 to 12,416 centipoise), spreadability (32.5 to 36.57 g × cm/s), pH (between 6 and 7), and drug content (93 to 95%). The results of the ex vivo permeation study proved significant improvement in drug permeation from optimized microsponge-loaded emulgel compared to the marketed formulation (f2 < 50).
Surface-engineered nanostructured lipid carrier systems for synergistic combination oncotherapy of non-small cell lung cancer
Shruti Rawal, Vivek Bora, Bhoomika Patel & Mayur Patel
doi : 10.1007/s13346-020-00866-6
Drug Delivery and Translational Research volume 11, pages2030–2051 (2021)
Nanoparticle-aided combination chemotherapy offers several advantages like ratiometric drug delivery, dose reduction, multi-targeted therapy, synergism, and overcoming multi-drug resistance. The current research was instigated to facilitate targeted and ratiometric co-delivery of docetaxel (DT) and curcumin (CR) through the development of folate (FA)–appended nanostructured lipid carriers (NLCs), i.e., FA-DTCR-NLCs to lung cancer cells. The FA-DTCR-NLCs were formulated by employing a scaleable and solvent-free high-pressure homogenization approach. The FA-DTCR-NLCs were evaluated for in vitro and in vivo characteristics using suitable analytical and statistical techniques. The FA-DTCR-NLCs demonstrated physicochemical properties and particokinetics suitable for targeted, ratiometric co-delivery of the anticancer agents. This was further affirmed by significantly better in vivo relative bioavailability of DT (24.85 fold) with FA-DTCR-NLCs as compared with Taxotere® (p < 0.05) and cell line studies. A significant tumor regression was observed from the results of tumor staging in a murine model of lung carcinoma (p < 0.05). Immunostaining of the tumor sections with tumor differentiation biomarkers suggested considerably higher apoptotic, anti-proliferative, anti-angiogenic, and anti-metastatic potential of FA-DTCR-NLCs compared with Taxotere®. In vivo toxicity assessment of the FA-DTCR-NLCs demonstrated a noteworthy reduction in DT associated side effects. The in vitro and in vivo pre-clinical findings prove the therapeutic and safety pre-eminence of FA-DTCR-NLCs for the treatment of NSCLC.
Co-delivery of cisplatin and siRNA through hybrid nanocarrier platform for masking resistance to chemotherapy in lung cancer
Vivek Patel, Rohan Lalani, Imran Vhora, Denish Bardoliwala, Akanksha Patel, Saikat Ghosh & Ambikanandan Misra
doi : 10.1007/s13346-020-00867-5
Drug Delivery and Translational Research volume 11, pages2052–2071 (2021)
The resistance of cancer cells to chemotherapy has presented a formidable challenge. The current research aims at evaluating whether silencing of the cisplatin efflux promoter gene ABCC3 using siRNA co-loaded with the drug in a nanocarrier improves its efficacy in non-small cell lung cancer (NSCLC). Hybrid nanocarriers (HNCs) comprising lipids and poly(lactic acid-polyethylene glycol) di-block copolymer (PEG-PLA) were prepared for achieving the simultaneous delivery of cisplatin caprylate and ABCC3-siRNA to the cancer cells. PEGylation of the formulated HNCs was carried out using post-insertion technique for imparting long circulation characteristics to the carrier. The optimized formulation exhibited an entrapment efficiency of 71.9 ± 2.2% and 95.83 ± 0.39% for cisplatin caprylate and siRNA respectively. Further, the HNC was found to have hydrodynamic diameter of 153.2 ± 1.76 nm and?+ 25.39 ± 0.49 mV zeta potential. Morphological evaluation using cryo transmission electron microscopy confirmed the presence of lipid bilayer surrounding the polymeric core in HNCs. The in vitro cellular uptake studies showed improved uptake, while cell viability studies of the co-loaded formulation in A549 cell-line indicated significantly improved cytotoxic potential when compared with drug solution and drug-loaded HNCs; cell cycle analysis indicated increased percentage of cell arrest in G2-M phase compared with drug-loaded HNCs. Further, the gene knock-down study showed that silencing of ABCC3 mRNA might be improved in vitro efficacy of the formulation. The optimized cisplatin and ABCC3 siRNA co-loaded formulation presented significantly increased half-life and tumour regression in A549 xenograft model in BALB/c nude mice. In conclusion, siRNA co-loaded formulation presented reduced drug resistance and increased efficacy, which might be promising for the current cisplatin-based treatments in NSCLC.
A novel amorphous solid dispersion based on drug–polymer complexation
Fan Meng, Rui Ferreira, Yongchao Su & Feng Zhang
doi : 10.1007/s13346-020-00869-3
Drug Delivery and Translational Research volume 11, pages2072–2084 (2021)
Rafoxanide (RAF) is a poorly water-soluble drug that forms a complex with povidone K25 (PVP) in a cosolvent system containing acetone and an alkaline aqueous medium. This study aims to investigate the impact of RAF-PVP complexation on in vitro and in vivo release of RAF. We prepared two RAF amorphous solid dispersions (ASDs) spray-dried from these two cosolvents. The first is a complexation-based spray-drying using a 70% 0.1 N NaOH solution with 30% acetone. The second is a traditional spray-dried formulation containing 80% acetone and 20% ethanol. Evidence from multiple solid-state characterization techniques indicated that ASDs spray-dried using both methods were amorphous. However, RAF ASDs based on drug–polymer complexation in the feed solution demonstrated not only faster drug release during dissolution testing but also higher in vivo absorption in an animal model. The improved RAF release in the complexation-based ASD is due to (1) high energy state of RAF owing to the amorphous form, (2) high pH in the microenvironment due to the ionized state of RAF and residual sodium hydroxide, (3) increased apparent solubility of RAF results from RAF–PVP complexation in dissolution media and biological media, and (4) improved wettability.
Preclinical evaluation of a hypotonic docetaxel nanosuspension formulation for intravesical treatment of non-muscle-invasive bladder cancer
Abhijit A. Date, Max Kates, Takahiro Yoshida, Taarika Babu, Umara Afzal, Pranjali Kanvinde, Alexander Baras, Nicole Anders, Ping He, Michelle Rudek, Justin Hanes, Trinity J. Bivalacqua & Laura M. Ensign
doi : 10.1007/s13346-020-00870-w
Drug Delivery and Translational Research volume 11, pages2085–2095 (2021)
Intravesical chemotherapy is a key approach for treating refractory non-muscle-invasive bladder cancer (NMIBC). However, the effectiveness of intravesical chemotherapy is limited by bladder tissue penetration and retention. Here, we describe the development of a docetaxel nanosuspension that, when paired with a low osmolality (hypotonic) vehicle, demonstrates increased uptake by the bladder urothelium with minimal systemic exposure. We compare the bladder residence time and efficacy in an immune-competent rat model of NMIBC to the clinical comparator, solubilized docetaxel (generic Taxotere) diluted for intravesical administration. We found that only the intravesical docetaxel nanosuspension significantly decreased cell proliferation compared to untreated tumor tissues. The results presented here suggest that the combination of nanoparticle-based chemotherapy and a hypotonic vehicle can provide more efficacious local drug delivery to bladder tissue for improved treatment of refractory NMIBC.
Effect of surfactant concentration and sterilization process on intraocular pressure–lowering activity of ?9-tetrahydrocannabinol-valine-hemisuccinate (NB1111) nanoemulsions
Corinne Sweeney, Narendar Dudhipala, Ruchi Thakkar, Tabish Mehraj, Sushrut Marathe, Waseem Gul, Mahmoud. A. ElSohly, Brian Murphy & Soumyajit Majumdar
doi : 10.1007/s13346-020-00871-9
Drug Delivery and Translational Research volume 11, pages2096–2107 (2021)
The use of ?9-tetrahydrocannabinol (THC) and ?9-tetrahydrocannabinol-valine-hemisuccinate (THC-VHS; NB1111) has recently been investigated in the management of intraocular pressure (IOP). The current study was undertaken to develop an optimized THC-VHS-loaded nanoemulsion formulation (NE; THC-VHS-NE) that could improve the drug load and duration of activity. THC-VHS-NE formulation was prepared by homogenization followed by ultrasonication. Sesame oil, Tween®80, and Poloxamer®188 were used as the oil, surfactant, and cosurfactant, respectively. Stability of the optimized THC-VHS-NE formulation was observed at 4 °C. The IOP lowering effect of the lead formulations, commercial timolol, and latanoprost ophthalmic solutions, as well as an emulsion in Tocrisolve™ (THC-VHS-TOC), was studied in New Zealand White rabbits following topical administration. The effect of surfactant concentration and sterilization process on IOP-lowering activity was also studied. THC-VHS-NE formulations (0.5, 1.0, and 2.0% w/v) showed dose dependent duration of action. The 1.0%w/v THC-VHS-NE formulation was selected for further evaluation because of its desirable physical and chemical characteristics. THC-VHS-NE formulation prepared with 2% w/v Tween®80 exhibited a higher drop in IOP than the 0.75 and 4.0% w/v of Tween®80 containing formulations. The IOP-lowering duration was, however, similar for the formulations with 0.75 and 2.0% Tween®80, while that with 4.0% Tween®80 was shorter. THC-VHS-NE formulation produced a greater drop in IOP (p < 0.05) and a longer duration of activity compared to THC-VHS-TOC, latanoprost, and timolol. The formulation could be sterilized by filtration without impacting product attributes. Overall, the optimized THC-VHS-NE formulation demonstrated a significantly better IOP reduction profile in the test model compared to the commercial ophthalmic solutions evaluated.
Microemulsion systems: from the design and architecture to the building of a new delivery system for multiple-route drug delivery
E. S. T. Egito, L. Amaral-Machado, E. N. Alencar & A. G. Oliveira
doi : 10.1007/s13346-020-00872-8
Drug Delivery and Translational Research volume 11, pages2108–2133 (2021)
Poorly soluble active pharmaceutical ingredients (APIs) create major problems in drug dosage form formulation resulting in significant delays in drug pharmaceutical screening, impairing the drug dosage form production. Aiming to minimize the use of excipients for increasing drug apparent solubility and, as a result, its bioavailability, exploration of innovative approaches is an earnest need. Microemulsion is an alternative drug delivery system that emerged as a valuable tool to achieve safe formulations for insoluble compounds and to improve their biopharmaceutical properties and pharmacokinetics. This review aims to present the state of the art of microemulsion systems, bringing an overview about their origin and how they can be properly produced and thoroughly characterized by different approaches. Furthermore, comments on regulatory issues regarding stability assessment and toxicity evaluation are discussed. The review concludes with a current opinion on microemulsion systems. The overall objective of this work was to describe all the potentialities of microemulsion systems as a drug carrier for therapeutic purposes, highlighting the unique features of this nanotechnological platform.
Computational modeling of intraocular drug delivery supplied by porous implants
Seyedalireza Abootorabi, Abhimanyu Tripathi, Huidan Whitney Yu & Lilian P. Dávila
doi : 10.1007/s13346-020-00878-2
Drug Delivery and Translational Research volume 11, pages2134–2143 (2021)
New and efficient drug delivery to the posterior part of the eye is a growing health necessity worldwide. Current treatment of eye diseases, such as age-related macular degeneration (AMD), relies on repeated intravitreal injections of drug-containing solutions. Such a drug delivery has major drawbacks including short drug life, significant medical service, and high medical cost. In this study, we explored a new approach to controlled drug delivery by introducing unique porous implants. Our computational modeling contained key physiological and anatomical traits. Incompressible flow in a porous media field, including the sclera, choroid, and retina layers, is governed by Darcy law and the time evolution of the drug concentration was solved via three convection–diffusion equations in the three layers, respectively. The computational model was validated by established results from independent studies and experimental data. Simulations of the IgG1 Fab drug delivery to the posterior eye were performed to evaluate the effectiveness of the porous implants for controlled delivery. Overall, our results indicate that drug therapeutic levels in the posterior eye sustain for eight weeks similarly to those using intravitreal injection. We first evaluated the effects of the porous implants on the drug delivery in the posterior layers. Subsequent simulations were carried out with varying porosity values in a porous episcleral implant. We found that the time evolution of drug concentration is distinctively correlated to drug source location and pore size. A correlation between porosity and fluid properties for selected porous implants was revealed for the first time in this study.
Sustained-hepatic arterial infusion of oxaliplatin: pharmacokinetic advantages over hepatic arterial infusion using a preclinical animal tumour model
Frederic Deschamps, Lambros Tselikas, Masako Tasaki, Shinji Motoyama, Thomas Isoardo, Michel Ducreux, Dragica Paunovic, Laurence Moine & Thierry de Baere
doi : 10.1007/s13346-020-00881-7
Drug Delivery and Translational Research volume 11, pages2144–2150 (2021)
Hepatic arterial infusion (HAI) of oxaliplatin allows greater liver tumour drug exposure compared to systemic infusion. However, the therapeutic index of HAI oxaliplatin remains poor. Using Pickering emulsion technology, we developed a platform able to provide sustained releases of oxaliplatin. The goal of this study was to evaluate the pharmacokinetic advantages of sustained-HAI oxaliplatin over HAI using a preclinical animal tumour model. Injections of 0.6 mg oxaliplatin in 20 min were selectively done in left hepatic arteries of 20 rabbits bearing a VX2 liver tumour in the middle left-lobe, using HAI (n = 10) or sustained-HAI (n = 10). In each group, half of the rabbits were sacrificed at 24 h and half at 72 h. Mass spectrometry was used to quantify drug pharmacokinetics in blood and oxaliplatin concentrations in tumour tissues, right- and middle left-liver lobes, spleen and lung. Compared to HAI, sustained-HAI of oxaliplatin resulted in lower plasmatic peak (Cmax: 275 ± 41 vs. 416 ± 133 ng/mL, p = 0.02) and higher concentration in the tumour at 24 h (2118 ± 2107 vs. 210 ± 93 ng/g, p = 0.008). After HAI, oxaliplatin concentration in tumours was significantly higher than in lung at 24 h (p = 0.03) but no other difference was found between oxaliplatin concentrations in tumours and in liver lobes, spleen or lung, neither at 24 h nor at 72 h. On the opposite, sustained-HAI resulted in higher concentrations of oxaliplatin in tumour compared to oxaliplatin concentrations in the middle left lobe (163 ± 86 ng/g at 24 h, p = 0.01, and 90 ± 15 ng/g at 72 h, p = 0.04), right lobe (174 ± 112 ng/g at 24 h, p = 0.01, and 112 ± 35 ng/g, p = 0.04 at 72 h), spleen (142 ± 21 ng/g at 24 h, p = 0.01, and 98 ± 12 ng/g at 72 h, p = 0.04), and lung (85 ± 11 ng/g at 24 h, p = 0.01, and 52 ± 4 ng/g at 72 h, p = 0.03). Sustained-HAI improves the therapeutic index of HAI oxaliplatin and offers a great potential for patients suffering from unresectable colorectal liver metastases or hepatocellular carcinoma.
3-O-Methylquercetin from Achyrocline satureioides—cytotoxic activity against A375-derived human melanoma cell lines and its incorporation into cyclodextrins-hydrogels for topical administration
Eduarda Doneda, Sara Elis Bianchi, Vanessa Pittol, Tainá Kreutz, Juliete Nathali Scholl, Irene L. Ibañez, Candelaria Bracalente, Hebe Durán, Fabrício Figueiró, Fábio Klamt & Valquiria Linck Bassani
doi : 10.1007/s13346-020-00882-6
Drug Delivery and Translational Research volume 11, pages2151–2168 (2021)
3-O-Methylquercetin (3OMQ), a natural 3-O-methylflavonoid, was isolated from Achyrocline satureioides and purified using the high-performance counter current chromatography (HPCCC) on a semi-preparative scale. High-purity 3OMQ (98%) was obtained with excellent recovery (81.8% (w/w)) and good yield (190 mg/100 g of plant). Isolated 3OMQ was evaluated against the A375 human amelanotic melanoma cancer cell line and A375-derived with different degrees of aggressiveness (A375-A7, A375-G10, and A375-PCDNA3). The results showed that 3OMQ reduced the cell viability of all strains, demonstrating time- and dose-dependent responses. 3OMQ was used to obtain hydrogels for the topical treatment of melanoma. Thus, 3OMQ was incorporated into hypromellose hydrogels with/without different cyclodextrins (CDs). The 3OMQ formulations showed permeation/retention in all skin layers, namely stratum corneum, epidermis, and dermis. A significant amount of 3OMQ was found in the replication site of the melanoma cells (epidermis and dermis). Altogether, these results demonstrate that 3OMQ can be isolated from Achyrocline satureioides by HPCCC on a semi-preparative scale and exhibit cytotoxic activity against melanoma cells. Its incorporation into an HPMC hydrogel containing HP-?-CD yielded a formulation with excellent technological and biopharmaceutical characteristics for evaluating the topical management of melanoma.
From the laboratory to the end-user: a primary packaging study for microneedle patches containing amoxicillin sodium
Emma McAlister, Mary-Carmel Kearney, E. Linzi Martin & Ryan F. Donnelly
doi : 10.1007/s13346-020-00883-5
Drug Delivery and Translational Research volume 11, pages2169–2185 (2021)
As microneedle (MN) patches progress towards commercialisation, there is a need to address issues surrounding their translation from the laboratory to the end-user. One important aspect of MN patches moving forward is appropriate primary packaging. This research focuses on MN patches containing amoxicillin (AMX) sodium for the potential treatment of neonatal sepsis in hot and humid countries. A MN patch consists of a hydrogel-forming MN array and a drug-containing reservoir. Improper primary packaging in hot and humid countries may result in degradation of active pharmaceutical ingredients, with the use of substandard medicines a major health concern. The research presented here, for the first time, seeks to investigate the integrity of MN patches in different primary packaging when stored under accelerated storage conditions, according to international guidelines. At pre-defined intervals, the performance of the MN patch was investigated. Major causes of drug instability are moisture and temperature. To avoid unnecessary degradation, suitable primary packaging was sought. After 168 days, the percentage of AMX sodium recovered from drug-containing reservoirs packaged in Protect™ 470 foil was 103.51 ± 7.03%. However, packaged in poly(ester) foil, the AMX sodium content decreased significantly (p = 0.0286), which is likely due to the degradation of AMX sodium by the imbibed moisture. Therefore, convincing evidence was provided as to the importance of investigating the stability of MN patches in primary packaging intended for MN-mediated transdermal delivery so that they are ‘fit for purpose’ when it reaches the end-user. Future work will include qualitative studies to assess MN patch usability.
Irinotecan and berberine co-delivery liposomes showed improved efficacy and reduced intestinal toxicity compared with Onivyde for pancreatic cancer
Xue Wang, Ying Liu, Wanjia Xu, Lirui Jia, Dongxu Chi, Jiang Yu, Jiamei Wang, Zhonggui He, Xiaohong Liu & Yongjun Wang
doi : 10.1007/s13346-020-00884-4
Drug Delivery and Translational Research volume 11, pages2186–2197 (2021)
Onivyde is the first irinotecan (IRI) nanoliposome that could improve pharmacokinetics and tumor biodistribution of irinotecan. Although FDA approves Onivyde for the treatment of pancreatic cancer patients who are not effective for GEM, the gastrointestinal toxicity caused by Onivyde is still a problem to be solved in clinical application. Berberine (BER), an isoquinolone alkaloid extracted from several different plants, has been reported to exhibit beneficial effect in alleviating intestinal mucositis and generating synergistic anticancer effect in combination with cytotoxic drugs. However, its therapeutic effect is affected by the different pharmacokinetic behavior of two drugs. Therefore, we utilized triethylamine-sucrose octasulfate gradient to construct nanoliposomes for co-delivery of irinotecan and berberine, termed as lipBI. This co-delivery nanoliposomes remained the synergistic ratio in the body and improved tumor distribution of IRI and BER. The lipBI significantly inhibited tumor growth in the BXPC-3 pancreatic cancer model compared with Onivyde (p < 0.05) and reduced the gastrointestinal toxicity in mice caused by IRI. Overall, IRI/BER co-loaded liposomes possessed great potential in the treatment of pancreatic cancer.
Effects of sustained GABA releasing implants on pancreatic islets in mice
Kevin C. Ling, D. Walker Hagan, Jorge Santini-González & Edward A. Phelps
doi : 10.1007/s13346-020-00886-2
Drug Delivery and Translational Research volume 11, pages2198–2208 (2021)
Gamma-aminobutyric acid (GABA) is an inhibitory neurotransmitter that is strongly and selectively synthesized in and secreted from pancreatic beta cells. Exogenously delivered GABA has been proposed to induce beta cell regeneration in type 1 diabetes, but these results have been difficult to replicate and may depend on the specifics of the animal model and drug delivery method used. Here, we developed a GABA-releasing ethylene-vinyl acetate polymer implant for sustained GABA delivery to the intraperitoneal space as an alternative to injected or oral GABA. We explored the effect of the GABA-releasing polymer implants compared to implanted osmotic pumps loaded with GABA on islet size in non-diabetic, outbred mice. We also attempted to monitor in vivo GABA release using HPLC on blood samples, but these measurements were confounded by high variability within treatment groups and unexpectedly high serum GABA levels in mice receiving GABA-negative implants. The ethylene-vinyl acetate polymer implants became heavily fibrosed with abdominal adhesion tissue, while the osmotic pumps had no macroscopic fibrosis. Histological analysis showed no significant effect of the sustained GABA delivery polymer or osmotic pumps on islet size, alpha cell to beta cell ratio, or the number of Ki67-positive islet cells. The GABA treatment time course was limited to two weeks due to the drug-release window of the polymer, while others reported islet-trophic effects of GABA after 10 to 12 weeks of treatment. In summary, our study is consistent with the concept that exogenous GABA administration does not significantly alter islet cell mass in non-diabetic CD-1 mice in the short-term. However, more data are needed including higher GABA doses and more prolonged treatment regimens for a better comparison with contrasting reports.
A new dual function orodissolvable/dispersible meclizine HCL tablet to challenge patient inconvenience: in vitro evaluation and in vivo assessment in human volunteers
Alaa Y. Darwesh, Marwa S. El-Dahhan & Mahasen M. Meshali
doi : 10.1007/s13346-020-00889-z
Drug Delivery and Translational Research volume 11, pages2209–2223 (2021)
Meclizine hydrochloride (MCZ), a first-generation antihistamine of the piperazine class, is antiemetic and intended for the management of nausea and vomiting with few adverse effects. The introduction of orodispersible tablet (ODT) would solve the problems encountered in the administration of this drug to pediatric, geriatric, and psychiatric patients. It would be even more advantageous if the MCZ tablet could provoke rapid and prolonged efficacy. Achieving concomitant rapid and prolonged drug therapeutic effects in orodissolvable/dispersible dosage forms would be challenging. In this respect, the authors prepared tablets with coats and cores for immediate and prolonged drug absorption. To achieve this goal, nanoparticles of MCZ from chitosan (CS) and shellac (SH) were prepared by ionic crosslinking and then directly compressed with excipients to form the core in a coated tablet. The immediate release coat with MCZ with the same excipients as in the core was amenable by direct compression. MCZ in the coat dissolved in the presence of a superdisintegrant, leading to rapid absorption from the buccal cavity. Meanwhile, enteric-coated nanoparticles were swallowed and dissolved in the GIT. Intuitively, the absorption process was prolonged. The in vitro release characteristics of all the tablets were studied in comparison with a commercial tablet (CT). Additionally, evaluation of the in vivo pharmacokinetic profile of both the prepared and commercial tablets was performed in humans. The dual function tablet disintegrated in 58 s at pH 5.5. In vivo, noncompartmental pharmacokinetic analysis showed concomitant rapid absorption, possibly from the coat, followed by prolonged absorption from the core. Successfully, these good results confirm that combined rapid and prolonged MCZ therapy with the prepared dual function orodissolvable/dispersible tablet could be a promising oral drug delivery system to enhance convenience for patients. Hopefully, dual function tablets will confer a benefit through the accommodation of more than a single medication in the case of multiple therapies.
A sustained release cysteamine microsphere/thermoresponsive gel eyedrop for corneal cystinosis improves drug stability
Jorge Jimenez, Michael A. Washington, Jayde L. Resnick, Ken K. Nischal & Morgan V. Fedorchak
doi : 10.1007/s13346-020-00890-6
Drug Delivery and Translational Research volume 11, pages2224–2238 (2021)
Cystinosis is a rare, metabolic, recessive genetic disease in which the intralysosomal accumulation of cystine leads to system wide organ and tissue damage. In the eye, cystine accumulates in the cornea as corneal cystine crystals and severely impacts vision. Corneal cystine crystals are treated with cysteamine eyedrops when administrated 6 to 12 times day and used within 1 week. The strict dosing regimen and poor stability are inconvenient and add to the burden of therapy. To reduce the dosing frequency and improve the stability, we present reformulation of cysteamine into a novel controlled release eyedrop. In this work, we characterize and evaluate a topical drug delivery system comprised of encapsulated cysteamine in polymer microspheres with a thermoresponsive gel carrier. Spray-dried encapsulation of cysteamine was performed. In vitro cysteamine release, stability, and ocular irritation and corneal permeation were evaluated. The data suggest that encapsulated cysteamine improves the stability to 7 weeks when compared with 1-week aqueous cysteamine eyedrops. Release studies from one drop of our system show that cysteamine release was present for 24 h and above the minimum cysteamine eyedrop amount (6 drops). Cysteamine from our system also resulted in negligible irritation and enhanced permeation when compared with traditional cysteamine eyedrops. In vivo studies were implemented to support ease of administration, tolerability, and retention for 24 h. These studies suggest that our controlled release delivery system may provide stable cysteamine from a safe, once daily gel eyedrop.
A new polymer-excipient for ethanol-resistant, sustained-release oral dosage forms
Thomas Endres, Christian Meier, Jan Hendrik Schattka, Claas Gronewold & Christian Moers
doi : 10.1007/s13346-020-00892-4
Drug Delivery and Translational Research volume 11, pages2239–2251 (2021)
The use of alcoholic beverages can cause uncontrolled release of drugs from sustained-release solid oral dosage forms and pose severe risks to patient health. The aim of this work was to design a new polymeric excipient with ethanol resistance inherent to the polymer. Polymers were systematically designed, manufactured via emulsion polymerization, and fully characterized. Glass transition temperatures between 10 and 18 °C and minimum film forming temperatures between 10 and 25 °C were chosen because these parameters are ideal for aqueous film-coating processing. Three model drug formulations were made with the new polymer excipients and tested in the presence and absence of ethanol. The concept of an alcohol resistance factor based on Weibull regression analysis was introduced. In vitro results confirmed the hypothesized structure-function relationship between comonomer composition and ethanol resistance. That is, nonionic hydrophilic functional groups interacted more strongly with the ethanolic solvent, as compared with cationic hydrophilic comonomer that interacted more strongly with the surrounding water molecules. The alcohol resistance factor varied between ? 44?±?2% (slower drug release in presence of ethanol) and +?34?±?0% (faster drug release in presence of ethanol) depending on the comonomer ratio. The main advantages of these new excipients compared with ethanol-resistant excipient blends include ease of use, plasticizers are not necessary, and shorter coating times.
Thiolated polymer nanocarrier reinforced with glycyrrhetinic acid for targeted delivery of 5-fluorouracil in hepatocellular carcinoma
Sachin S. Bhat, Dhrubojyoti Mukherjee, Pinal Sukharamwala, Rachita Dehuri, Anita Murali & Banala Venkatesh Teja
doi : 10.1007/s13346-020-00894-2
Drug Delivery and Translational Research volume 11, pages2252–2269 (2021)
The present work investigates the targeting efficacy of a novel thiolated polymer-based nanocomposite reinforced with glycyrrhetinic acid (GA) and loaded with 5-fluorouracil in hepatocellular carcinoma (HCC). The thiolated polymers were synthesized by EDAC-mediated conjugation reactions and lyophilization. The nanoparticles were prepared by solvent diffusion and high-pressure homogenization method. The prepared nanocomposite was characterized by Fourier transform infrared (FTIR) radiation, x-ray diffraction (XRD), dynamic light scattering (DLS), scanning electron microscopy (SEM) and atomic force microscopy (AFM) techniques. Pharmacological evaluation of the formulation was carried out on a rat model of diethylnitrosamine (DEN), and carbon tetrachloride (CCl4)-induced HCC and MTT assay was carried out with HEP-G2 cell line. In silico studies were conducted to investigate the probable mechanistic pathway of the nanocomposite. FTIR and XRD analysis indicated the successful thiolation of the polymers and confirmed the formation of the nanocomposite without any incompatibilities. DLS, SEM/EDX and AFM characterization confirmed that the nanoparticles were within the nano-size range. MTT assay implied the cytotoxic nature of the nanocomposite against hepatic carcinoma cells. The in vivo study revealed that serum SGOT, SGPT, ALP, GGT and total bilirubin levels were significantly reduced, in comparison with disease control and the result was confirmed by histopathology studies. The results of the HPLC analysis of liver homogenate confirmed the liver targeting ability of the nanocomposite. In silico studies exhibited significant binding affinity of GA and thiolated Eudragit towards liver homolog receptor-1 (LRH-1) suggesting that the developed nanocomposite could be a potential material for the treatment of HCC.
