QbD-based co-loading of paclitaxel and imatinib mesylate by protamine-coated PLGA nanoparticles effective on breast cancer cells.

Aim: Paclitaxel and imatinib mesylate are drugs used in the treatment of breast cancer. Conventional drug-delivery systems have limitations in the effective treatment of breast cancer using the drugs. Materials & methods: Combination index studies were used to identify the optimum ratio of both drugs showing maximum synergistic effect. Using a systematic quality-by-design approach, protamine-coated PLGA nanoparticles co-loaded with paclitaxel and imatinib mesylate were formulated. Further characterization and cell line evaluations were performed. Results: Encapsulation efficiency obtained was 92.54% for paclitaxel and 75.12% for imatinib mesylate. A sustained (24 h) and controlled zero-order drug release was obtained. Conclusion: Formulated nanoparticles had a low IC50 value and enhanced cellular uptake.

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Central composite design augmented quality-by-design-based systematic formulation of erlotinib hydrochloride-loaded chitosan-poly (lactic-co-glycolic acid) nanoparticles.

Aim: This study aimed to formulate erlotinib hydrochloride (ERT-HCL)-loaded chitosan (CS) and poly (lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) using Quality-by-Design (QbD) to optimize critical quality attributes (CQAs). Materials & methods: Quality target product profile (QTPP) and CQAs were initially established. Based on L8-Taguchi screening and risk assessments, central composite design (CCD) design was used to optimize NPs. Results: ERT-HCL-loaded CS-PLGA NPs had a mean particle diameter, zeta potential and entrapment efficiency of 226.50 ± 1.62 d.nm, 27.66 ± 0.64 mV and 78.93 ± 1.94 %w/w, respectively. The NPs exhibited homogenous spherical morphology and sustained release for 72 h. Conclusion: Using systematic QbD approach, ERT-HCL was encapsulated in CS-PLGA NPs, optimizing CQAs. These findings propel future research for improved NSCLC treatment.

Innovative erlotinib-loaded chitosan-PLGA nanoparticles, developed through a systematic QbD approach, promise enhanced drug delivery for NSCLC. Optimized for size, potential and entrapment efficiency, these particles demonstrate sustained release over 72 h. #DrugDelivery #QBD #NSCLC.

Temozolomide nano-in-nanofiber delivery system with sustained release and enhanced cellular uptake by U87MG cells.

OBJECTIVE: The study was aimed at formulating temozolomide (TMZ) loaded gelatin nanoparticles (GNPs) encapsulated into polyvinyl alcohol (PVA) nanofibers (TMZ-GNPs-PVA NFs) as the nano-in-nanofiber delivery system. The secondary objective was to explore the sustained releasing ability of this system and to assess its enhanced cellular uptake against U87MG glioma cells in vitro. SIGNIFICANCE: Nano-in-nanofibers are the emerging drug delivery systems for treating a wide range of diseases including cancers as they overcome the challenges experienced by nanoparticles and nanofibers alone. METHODS: The drug-loaded GNPs were formulated by one-step desolvation method. The Design of Experiments (DoE) was used to optimize nanoparticle size and entrapment efficiency. The optimized drug-loaded nanoparticles were then encapsulated within nanofibers using blend electrospinning technique. The U87MG glioma cells were used to investigate the uptake of the formulation. RESULTS: A 32 factorial design was used to optimize the mean particle size (145.7 nm) and entrapment efficiency (87.6%) of the TMZ-loaded GNPs which were subsequently ingrained into PVA nanofibers by electrospinning technique. The delivery system achieved a sustained drug release for up to seven days (in vitro). The SEM results ensured that the expected nano-in-nanofiber delivery system was achieved. The uptake of TMZ-GNPs-PVA NFs by cells was increased by a factor of 1.964 compared to that of the pure drug. CONCLUSION: The nano-in-nanofiber drug delivery system is a potentially useful therapeutic strategy for the management of glioblastoma multiforme.

Inhalable spray-dried polycaprolactone-based microparticles of Sorafenib Tosylate with promising efficacy on A549 cells.

The study developed and evaluated Sorafenib Tosylate (SRT)-loaded polymeric microparticles (MPs) using biodegradable polymer polycaprolactone (PCL) as a potential inhalable carrier for NSCLC. MPs were prepared by spray-drying an oil-in-water (o/w) emulsion. The optimized MPs demonstrated excellent flowability, particle size of 2.84 ± 0.5 µm, zeta potential of -14.0 ± 1.5 mV, and 85.08 ± 5.43% entrapment efficiency. ATR-FTIR/DSC studies revealed a lack of characteristic peaks of the crystalline drug signifying good entrapment of the drug. MPs were spherical and uniform in SEM pictures. The MPs showed a biphasic release pattern up to 72h. The Anderson cascade impactor (ACI) investigation demonstrated the highest drug deposition at stage 4, which revealed that the MPs can reach the lungs' secondary and terminal bronchi. Inhalable MPs had an efficient aerodynamic property with a mass median aerodynamic diameter (MMAD) of 2.63 ± 1.3 µm, a geometric standard deviation (GSD) of 1.93 ± 0.2 µm, and a fine particle fraction (FPF) of 87 ± 2.5%. Finally, in cytotoxicity studies on A549 cancer cells, MPs had an IC50 value of 0.6011 ± 0.8 µM, which was 85.68% lower than free drug. These findings suggest SRT-loaded inhalable PCL-based MPs as a novel NSCLC treatment.

Fragmented antibodies in non-small cell lung cancer: A novel nano-engineered delivery system for detection and treatment of cancer.

Non-small cell lung cancer (NSCLC) has a long history of defying traditional cytotoxic treatment. Significant advancements in biotechnology, cancer biology, and immunotherapy have provided new insights that have altered the landscape for the management of NSCLC, clearing the way for a new era of pharmaceuticals in the form of monoclonal antibodies and their fragments. Antibody fragments are superior to monoclonal antibodies because of their small size, which allows them to penetrate cells and tissues effectively. When combined with functional nanocarriers, antibody fragments can target cancer cells while offering improved efficacy and fewer off-target effects. We discuss current topics of interest including anti-CTLA-4 mAbs, Talactoferrin alfa (TLF), and the CYFRA 21-1 biomarker, with brief insights into its novel detection system.

Multifunctional nanocarriers for delivering siRNA and miRNA in glioblastoma therapy: advances in nanobiotechnology-based cancer therapy.

Glioblastoma multiforme (GBM) is one of the most lethal cancer due to poor diagnosis and rapid resistance developed towards the drug. Genes associated to cancer-related overexpression of proteins, enzymes, and receptors can be suppressed using an RNA silencing technique. This assists in obtaining tumour targetability, resulting in less harm caused to the surrounding healthy cells. RNA interference (RNAi) has scientific basis for providing potential therapeutic applications in improving GBM treatment. However, the therapeutic application of RNAi is challenging due to its poor permeability across blood-brain barrier (BBB). Nanobiotechnology has evolved the use of nanocarriers such as liposomes, polymeric nanoparticles, gold nanoparticles, dendrimers, quantum dots and other nanostructures in encasing the RNAi entities like siRNA and miRNA. The review highlights the role of these carriers in encasing siRNA and miRNA and promising therapy in delivering them to the glioma cells.

Nanoparticles incorporated in nanofibers using electrospinning: A novel nano-in-nano delivery system.

Nanofibers are cutting-edge drug delivery systems that are being utilised to treat a variety of ailments. Nanofibers are mostly woven by electrospinning techniques that are majorly used in drug delivery, wound dressing, tissue engineering, sensors, etc. They have several limitations that can be addressed by developing nano-in-nano delivery techniques. Nanoparticles are incorporated into nanofibers in these nano-in-nano systems. They offer a lot of benefits over other nanosystems, including the ability to shield drugs from physical deterioration, the ability to provide prolonged drug release, high surface area to volume ratio, increased drug loading capacity and the potential to be employed in critical conditions such as cancer. These nanoparticles can be encapsulated, entrapped, or adsorbed onto nanofibers in a variety of ways. To include nanosystems into nanofibers, a variety of materials and different kinds of nanoparticles can be used. The present review gives an insight to the applications of nano - in - nano drug delivery system for different diseases/disorders. The review also brings forward the current state of these novel delivery systems along with future perspectives.

Temozolomide nano enabled medicine: promises made by the nanocarriers in glioblastoma therapy.

Glioblastoma multiforme (GBM) is abnormal cell proliferation of glial cells. GBM is the grade IV glioma brain cancer which is life-threatening to many individuals affected by this cancer. The DNA alkylating agent Temozolomide (TMZ) has the distinctiveness of being FDA approved anticancer drug for the first line treatment for GBM. However, treatment of GBM still remains a challenge. This is attributed to TMZ's toxic nature, severe side effects, and fast degradation in vivo. In addition, the lack of targeting ability increases the chances of systemic toxicities. A nano enabled targeted delivery system not only improves the efficiency of TMZ by making it cross the blood brain barrier, have specificity to target, but also reduces toxicity to healthy tissues. Over the last decade the significant advances in the area of nanotechnology applied to medicine have developed many multifunctional therapeutics. In this context, the present review article comprehends the significant progress in the field of TMZ loaded nanocarriers showing promise for futuristic nanomedicine therapies in treating GBM.

Targeted drug therapy in non-small cell lung cancer: Clinical significance and possible solutions-Part I.

INTRODUCTION: Non-small cell lung cancer (NSCLC) comprises of 84% of all lung cancer cases. The treatment options for NSCLC at advanced stages are chemotherapy and radiotherapy. Chemotherapy involves conventional nonspecific chemotherapeutics, and targeted-protein/receptor-specific small molecule inhibitors. Biologically targeted therapies such as an antibody-based immunotherapy have been approved in combination with conventional therapeutics. Approved targeted chemotherapy is directed against the kinase domains of mutated cellular receptors such as epidermal growth factor receptor (EGFR), anaplastic lymphoma kinases (ALK), neurotrophic receptor kinases (NTRK) and against downstream signaling molecules such as BRAF (v-raf murine sarcoma viral oncogene homolog B1). Approved biologically targeted therapy involves the use of anti-angiogenesis antibodies and antibodies against immune checkpoints. AREAS COVERED: The rationale for the employment of targeted therapeutics and the resistance that may develop to therapy are discussed. Novel targeted therapeutics in clinical trials are also included. EXPERT OPINION: Molecular and histological profiling of a given tumor specimen to determine the aberrant onco-driver is a must before deciding a targeted therapeutic regimen for the patient. Periodic monitoring of the patients response to a given therapeutic regimen is also mandatory so that any semblance of resistance to therapy can be deciphered and the regimen may be accordingly altered.

Targeted drug therapy in nonsmall cell lung cancer: clinical significance and possible solutions-part II (role of nanocarriers).

INTRODUCTION: Nonsmall cell lung cancer (NSCLC) accounts for 80-85% of the cases of lung cancer. The conventional therapeutic effective dosage forms used to treat NSCLC are associated with rigid administration schedules, adverse effects, and may be associated with acquired resistance to therapy. Nanocarriers may provide a suitable alternative to regular formulations to overcome inherent drawbacks and provide better treatment modalities for the patient. AREAS COVERED: The article explores the application of drug loaded nanocarriers for lung cancer treatment. Drug-loaded nanocarriers can be modified to achieve controlled delivery at the desired tumor infested site. The type of nanocarriers employed are diverse based on polymers, liposomes, metals and a combination of two or more different base materials (hybrids). These may be designed for systemic delivery or local delivery to the lung compartment (via inhalation). EXPERT OPINION: Nanocarriers can improve pharmacokinetics of the drug payload by improving its delivery to the desired location and can reduce associated systemic toxicities. Through nanocarriers, a wide variety of therapeutics can be administered and targeted to the cancerous site. Some examples of the utilities of nanocarriers are codelivery of drugs, gene delivery, and delivery of other biologics. Overall, the nanocarriers have promising potential in improving therapeutic efficacy of drugs used in NSCLC.

An outlook on procedures of conjugating folate to (co)polymers and drugs for effective cancer targeting.

Folate receptors (FRs) are expressed in vast majority of cancers. Selective targeting of the FRs is, therefore, one of the most popular and sought-after strategies for improving the efficacy of cancer therapeutics. Variety of approaches involving folate conjugation to several well-known and novel, nontoxic, biodegradable, and biocompatible (co)polymers have been attempted and successfully applied to a large number of nanoparticulate drug delivery systems (micelles, liposomes, nanoparticles, quantum dots, mesoporous silica-based materials, and others) in the last decade-and-a-half. Standard and novel synthetic approaches were utilized for the conjugation, followed by the formulation of the drug delivery modality. In most of the cases, the targeted system lived up to its reputation, validating its usefulness in targeted cancer therapeutics. The present review summarizes the progress and state-of-the-art synthetic methodologies for folate conjugation to (co)polymers, drugs, and nucleic acids. The limitations of the FR targeting are discussed in brief to give the reader the other side of the story. Finally, the information on marketed folic acid conjugates highlight their industrial applications.

Quality by design (QbD) approach in processing polymeric nanoparticles loading anticancer drugs by high pressure homogenizer.

Polymeric nanoparticles prepared using high pressure homogenizer (HPH) present some unique challenges during manufacturing which can be better understood by application of quality by design (QbD) approaches. The present review highlights the ways to identify the critical material attributes which includes the anticancer drugs, polymers, surfactants, solvent system and dispersion system. A comprehensive understanding of the critical processing parameters like pressure and number of cycles during the working of HPH used in putting forward the critical quality attributes such as size, shape, surface charge or droplet stabilization. Such QbD approach will involve development of an effective control strategy for would ensure safe encapsulation of anticancer drugs for successful product development. Proper addressing of the issues related to scaling-up would lead to successful commercialization of the nano-sized formulations loaded with anticancer drugs.

Understanding the biology and advent of physics of cancer with perspicacity in current treatment therapy.

Cancer has become a key healthcare problem worldwide. The background of cancer research has brought the advent of cross-disciplinary collaborations that has enabled us to get an idea of the disease mechanisms at spatial and temporal scales. Understanding the combination of biology and physics of cancer presents a promising field of research with apprehensions in better clarity over both cellular and molecular mechanisms impacting cancer therapy. Investigation of cancer biology has provided a wealth of knowledge on cancer initiation and propagation and has provided newer treatment strategies in the fight against cancer. Understanding the physics of cancer provides wonderful set of equations that take advantage of mechanisms of force production, propagation by the cancer cells and mechanical properties of the tumor tissue. The spatial tissue arrangement in which the tumor growth occurs can be better understood with biophysics. Thus, the combination of biology and physics of cancer contributes crucially in impacting the correct treatment of cancer. The present review is aimed at providing an overview of regulatory networks, regulation of cell division and differentiation, the signal transduction pathways and integration of all sciences including physics, biology, and medicine which is very well needed to tackle the war against cancer and thus influence cancer therapy. These circuits will help us understand whether the therapy will work wonders or cause failure. As cancer is much more than a genetic disease, more insights into the malignancy with physical approaches are designed to use cancer therapy effectively.

Implantable drainage devices in glaucoma: Quo vadis?

Glaucoma, a gradually progressive class of either chronic eye disease or disorder, occurs due to increasing intra-ocular pressure. To reduce glaucoma, it is essential to stop the progression of IOP in the eye which is achieved by medical treatment, laser treatment and surgery. Profuse conventional drugs and laser surgeries are the primary go-tos for decreasing IOP. However, presently available marketed formulations using anti-glaucoma drugs have issues of either difficulty in crossing the blood retinal barrier (BRB) or lower systemic bioavailability. Hence, the drugs having lower therapeutic index would need to be administered frequently. This repeated systemic administration of high doses of drugs eventually leads to side effects, damage to the eye as well as patient noncompliance. Implants are deemed to be the suitable treatment left when such side effects are to be avoided. An eye implant is one of the choices for restoring the volume of the eye socket following evisceration and enucleation. Implantable drainage devices (IDD) aka glaucoma drainage devices (GDDs) or aqueous shunts are small reconstructive surgery devices, either solid or made of a tube fixed to an endplate. The premonition behind implants is augmenting standard glaucoma surgery which successfully is attained by surgically creating a drainage opening and positioning the device properly on it. All implants are made with an objective of decreasing IOP by enhancing the fluid outflow from the eye. A critical comparison is made among different implants like Molteno: single-plate and Double-plate, Baerveldt drainage implant, Schocket implant, Ex-Press R50 implant, Ahmed glaucoma valve, Krypton implant to the latest one's including iStent, iStent inject, Hydrus, CyPass, XEN and InnFocus.

E-drug delivery: a futuristic approach.

Drug delivery systems are undergoing technology changes to enhance patient comfort and compliance. Electronic drug delivery (E-drug delivery) systems are being developed to regulate drug dose delivery by easy monitoring of doses, especially in chronic and age-related diseases. E-drug delivery can monitor the correct dose of anesthesia, could be used in GI tracking by E-capsules, in epilepsy, insulin drug delivery, cardiac ailments and cancer therapy. Wearable E-drug delivery systems and Smartphone apps are the new additions. In this review, the authors attempt to highlight how technology is changing for improved patient comfort and treatment. Personalized drug delivery systems will be the future treatment process in healthcare.

Polymers, responsiveness and cancer therapy.

A single outcome in a biological procedure at the time of cancer therapy is due to multiple changes happening simultaneously. Hence to mimic such complex biological processes, an understanding of stimuli responsiveness is needed to sense specific changes and respond in a predictable manner. Such responses due to polymers may take place either simultaneously at the site or in a sequential manner from preparation to transporting pathways to cellular compartments. The present review comprehends the stimuli-responsive polymers and multi-responsiveness with respect to cancer therapy. It focuses on the exploitation of different stimuli like temperature, pH and enzymes responsiveness in a multi-stimuli setting. Nanogels and micelles being two of the most commonly used responsive polymeric carriers have also been discussed. The role of multiple stimuli delivery system is significant due to multiple changes happening in the near surroundings of cancer cells. These responsive materials are able to mimic some biological processes and recognize at the molecular level itself to manipulate development of custom-designed molecules for targeting cancer cells.

Design of Experiments (DoE) Approach to Optimize the Sustained Release Microparticles of Gefitinib.

BACKGROUND: Gefitinib (GEF), the kinase inhibitor, is presently available as tablets to be taken orally in high doses of 250-500 mg per day due to its poor solubility. The solubility issues affect not only its onset of action but also the bioavailability. These drawbacks foresight the need to have an alternate dosage form, preferably a sustained release formulation. METHODS: In the present study, microparticles were prepared by emulsion solvent evaporation using PLGA 50:50 (GEF-PLGA MP). A 32 factorial design was used to optimize the critical quality parameters to the set mean particle size in the range of 7.4±2.5 µm and entrapment efficiency of 80%. SEM microscopy of the prepared microparticles confirmed to have a spherical smooth shape. The GEFPLGA- MPs sustained the release of GEF for 72 hours. The first-order kinetics ruled the mechanism of drug release and was predicted to follow Fickian diffusion. RESULT: Anticancer efficacy was judged by the cytotoxicity studies using the L132 lung cancer cells. MTT assay showed 3-fold enhanced cytotoxicity of GEF loaded microparticles against L132 cells as compared to plain GEF. CONCLUSION: It was concluded that gefitinib can be efficiently loaded into the biodegradable polymer PLGA to provide sustained release of the drug.

Nanogels as potential nanomedicine carrier for treatment of cancer: A mini review of the state of the art.

Nanogels are being explored as drug delivery agents for targeting cancer due to their easy tailoring properties and ability to efficiently encapsulate therapeutics of diverse nature through simple mechanisms. Nanogels are proficiently internalized by the target cells, avoid accumulating in nontarget tissues thereby lower the therapeutic dosage and minimize harmful side effects. However, there is an urgent need for relevant clinical data from nanogels so as to allow translation of the nanogel concept into a viable therapeutic application for the treatment of cancer. This review highlights some of the recent progress in nanogels as a carrier in the field of nanomedicine for the treatment of cancer. The present review critically analyzes the use of extracellular pH targeting for nanogels, siRNA delivery, PEGylated nanogels, multi-responsive nanogels and intracellular delivery of nanogels for improved therapy of cancer.

Applications of nanoparticles in treatment and diagnosis of leukemia.

The conventional chemotherapy for leukemia involves frequent dosing, severe side effects and lack of specificity of such anticancer drugs. The treatment with most of the anti-leukemic drugs would be improved if they were delivered to their biological targets through appropriate application of nanotechnology by manipulating at the molecular level. Nanoparticles in the recent years have shown tremendous application with respect to diagnosis and treatment of leukemia. The review specifically focuses on the use of nanoparticles for sustaining the release of anti-leukemic drugs and intracellular delivery of such nanoparticles. The review also highlights the application of nanoparticles in reversal of multidrug resistance.

High encapsulation efficiency of poloxamer-based injectable thermoresponsive hydrogels of etoposide.

CONTEXT: Hydrogels are promising polymeric network capable of sustaining the release of drug but have a major limitation for encapsulation of hydrophobic drugs. OBJECTIVE: This study was undertaken to encapsulate etoposide in poloxamer 407-based thermosensitive hydrogels with an aim to sustain its release. MATERIALS AND METHODS: Etoposide-loaded hydrogels were prepared by the cold method and optimized for encapsulation efficiency (EE) by a 3(2) factorial design. Poloxamer 407-poloxamer 188 hydrogel (E-P407-P188) and poloxamer 407-poly(ethylene glycol) (E-P407-PEG) hydrogel were characterized for SEM, swelling, sol-gel phase transition and injectability study. RESULTS AND DISCUSSION: In E-P407-P188 hydrogel the EE of 75% could be obtained and in E-P407-PEG hydrogels the EE was 84%. The SEM images showed a porous structure. The release of ETO was sustained up to 48 h by E-P407-PEG hydrogel and 24 h by E-P407-P188 hydrogel. The drug release was governed by first-order kinetics and followed Fickian diffusion mechanism in both the cases. CONCLUSION: Such injectable thermosensitive hydrogel of etoposide could be effectively used for continuous release of drug to the tumor and surrounding tissues.