In-depth Mechanism, Challenges, and Opportunities of Delivering Therapeutics in Brain Using Intranasal Route.

Central nervous system-related disorders have become a continuing threat to human life and the current statistic indicates an increasing trend of such disorders worldwide. The primary therapeutic challenge, despite the availability of therapies for these disorders, is to sustain the drug's effective concentration in the brain while limiting its accumulation in non-targeted areas. This is attributed to the presence of the blood-brain barrier and first-pass metabolism which limits the transportation of drugs to the brain irrespective of popular and conventional routes of drug administration. Therefore, there is a demand to practice alternative routes for predictable drug delivery using advanced drug delivery carriers to overcome the said obstacles. Recent research attracted attention to intranasal-to-brain drug delivery for promising targeting therapeutics in the brain. This review emphasizes the mechanisms to deliver therapeutics via different pathways for nose-to-brain drug delivery with recent advancements in delivery and formulation aspects. Concurrently, for the benefit of future studies, the difficulties in administering medications by intranasal pathway have also been highlighted.

Nano-nutraceuticals to Combat Oxidative Stress: Unlocking Newer Paradigms in Adjuvant Therapy.

Nutraceuticals are products that provide both nutritional and therapeutic benefits. These compounds can slow the aging process and provide physiological effects shielding individuals from acute and chronic diseases. People's interests have shifted from allopathic to Ayurvedic to nutraceuticals in recent years. These are often common dietary supplements that have drawn customers worldwide because of their high nutritional safety and lack of adverse effects when used for a long time. Although conventional dosage forms, including pills, tablets, and semi-solids, are still available, they nevertheless have poorer bioavailability, less stability, and less effectiveness for targeted delivery of bioactives. The use of effective nanocomplex systems as nano-antioxidants using nanotechnology has become a promising field. Among its many uses, nanotechnology is mostly used to create foods and nutraceuticals that are more bioavailable, less toxic, and more sustainable. Additionally, it has been emphasized how precisely nano-pharmaceuticals for oxidative stress produce the desired effects. These improvements show improved antioxidant delivery to the target region, reduced leakage, and increased targeting precision. The outcomes demonstrated that oxidative stress-related illnesses can be effectively treated by lowering ROS levels with the use of nanonutraceuticals. The major ideas and uses of nano-nutraceuticals for health are outlined in this review, with an emphasis on reducing oxidative stress.

Terpenoids as potential phytoconstituent in the treatment of diabetes: From preclinical to clinical advancement.

BACKGROUND: Diabetes mellitus, a hyperglycemic condition associated with multitudinous organ dysfunction, is a hallmark of the metabolic disorder. This life-threatening condition affects millions of individuals globally, harming them financially, physically and psychologically in the course of therapy. PURPOSES: The course therapy for illnesses has undergone ground-breaking transformations due to recent technical advances and insights. Alternatively, the administration of hyperglycemia-reducing agents results in several complications, including severe cardiovascular disease, kidney failure, hepatic problems, and several dermatological conditions. Consideration of alternate diabetic therapy having minimal side effects or no adverse reactions has been driven by such problems. STUDY DESIGN: An extensive literature study was conducted in authoritative scientific databases such as PubMed, Scopus, and Web of Science to identify the studies elucidating the bioactivities of terpenoids in diabetic conditions. METHODS: Keywords including 'terpenoids', 'monoterpenes', 'diterpenes', 'sesquiterpenes', 'diabetes', 'diabetes mellitus', 'clinical trials', 'preclinical studies', and 'increased blood glucose' were used to identify the relevant research articles. The exclusion criteria, such as English language, duplication, open access, abstract only, and studies not involving preclinical and clinical research, were set. Based on these criteria, 937 relevant articles were selected for further evaluation. RESULTS: Triterpenes can serve as therapeutic agents for diabetic retinopathy, peripheral neuropathy, and kidney dysfunction by inhibiting several pathways linked to hyperglycemia and its complications. Therefore, it is essential to draw special attention to these compounds' therapeutic effectiveness and provide scientific professionals with novel data. CONCLUSION: This study addressed recent progress in research focussing on mechanisms of terpenoid, its by-products, physiological actions, and therapeutic applications, particularly in diabetic and associated disorders.

Nanoneuroscience: Cutting-edge Approach for Disease Management.

Neurological disorders (ND) have affected a major part of our society and have been a challenge for medical and biosciences for decades. However, many of these disorders haven't responded well to currently established treatment approaches. The fact that many active pharmaceutical ingredients can't get to their specified action site inside the body is one of the main reasons for this failure. Extracellular and intracellular central nervous system (CNS) barriers prevent the transfer of drugs from the blood circulation to the intended location of the action. Utilizing nanosized drug delivery technologies is one possible way to overcome these obstacles. These nano-drug carriers outperform conventional dosage forms in many areas, including good drug encapsulation capacity, targeted drug delivery, less toxicity, and enhanced therapeutic impact. As a result, nano-neuroscience is growing to be an intriguing area of research and a bright alternative approach for delivering medicines to their intended action site for treating different neurological and psychiatric problems. In this review, we have included a short overview of the pathophysiology of neurological diseases, a detailed discussion about the significance of nanocarriers in NDs, and a focus on its recent advances. Finally, we highlighted the patented technologies and market trends, including the predictive analysis for the years 2021-2028.

Potential molecular pathways of angiotensin receptor blockers in the brain toward cognitive improvement in dementia.

The alarming rise of cognitive impairment and memory decline and limited effective solutions present a worldwide concern for dementia patients. The multivariant role of the renin-angiotensin system (RAS) in the brain offers strong evidence of a role for angiotensin receptor blockers (ARBs) in the management of memory impairment by modifying glutamate excitotoxicity, downregulating inflammatory cytokines such as interleukin (IL)-1ß, IL-6 and tumor necrosis factor (TNF)α, inhibiting kynurenine aminotransferase (KAT)-II, nucleotide-binding domain, leucine-rich-containing family and pyrin-domain-containing-3 (NLRP3) inflammasomes, boosting cholinergic activity, activating peroxisome proliferator-activated receptor (PPAR)-γ, countering cyclooxygenase (COX) and mitigating the hypoxic condition. The present work focuses on the intricate molecular mechanisms involved in brain-RAS, highlighting the role of ARBs, connecting links between evidence-based unexplored pathways and investigating probable biomarkers involved in dementia through supported preclinical and clinical literature.

The SH-SY5Y cell line: a valuable tool for Parkinson's disease drug discovery.

INTRODUCTION: Owing to limited efficient treatment strategies for highly prevalent and distressing Parkinson's disease (PD), an impending need emerged for deciphering new modes and mechanisms for effective management. SH-SY5Y-based in vitro neuronal models have emerged as a new possibility for the elucidation of cellular and molecular processes in the pathogenesis of PD. SH-SY5Y cells are of human origin, adhered to catecholaminergic neuronal attributes, which consequences in imparting wide acceptance and significance to this model over conventional in vitro PD models for high-throughput screening of therapeutics. AREAS COVERED: Herein, the authors review the SH-SY5Y cell line and its value to PD research. The authors also provide the reader with their expert perspectives on how these developments can lead to the development of new impactful therapeutics. EXPERT OPINION: Encouraged by recent research on SH-SY5Y cell lines, it was envisaged that this in vitro model can serve as a primary model for assessing efficacy and toxicity of new therapeutics as well as for nanocarriers' capacity in delivering therapeutic agents across BBB. Considering the proximity with human neuronal environment as in pathogenic PD conditions, SH-SY5Y cell lines vindicated consistency and reproducibility in experimental results. Accordingly, exploitation of this standardized SH-SY5Y cell line can fast-track the drug discovery and development path for novel therapeutics.

Chitosan and hyaluronic acid-based nanocarriers for advanced cancer therapy and intervention.

Cancer has become a major public health issue leading to one of the foremost causes of morbidity and death in the world. Despite the current advances in diagnosis using modern technologies and treatment via surgery or chemo- and radio-therapies, severe side effects or after-effects limit the application of these treatment modalities. Novel drug delivery systems have shown the potential to deliver chemotherapeutics directly to cancer cells, thus minimizing unnecessary exposure to healthy cells. Concurrently, to circumvent difficulties associated with conventional deliveries of cancer therapeutics, natural polysaccharides have gained attention for the fabrication of such deliveries owing to biocompatibility, low toxicity, and biodegradability. It has been exhibited that natural polysaccharides can deliver high therapeutic concentrations of the entrapped drug to the target cells by sustained and targeted release. Considering the immense potential of natural polymers, the present work focuses on naturally generated biopolymer carriers based on chitosan and hyaluronic acid. This review delineated on the role of chitosan and its derivation from renewable resources as a biocompatible, biodegradable, nonimmunogenic material with notable antitumor activity as a drug delivery carrier in oncotherapy. Moreover, hyaluronic acid, itself by its structure or when linked with other molecules contributes to developing promising pharmaceutical delivery systems to setback the restrictions related to conventional cancer treatment.

Nano-approaches and Recent Advancements in Strategies to Combat Challenges Associated with Thyroid Cancer Therapies.

The prevalence of thyroid cancer (TC) is more common in women and is up to 43% in patients aged between 45-65 years. The battle against TC is hampered by the lack of effective diagnostic and therapeutic approaches. The effectiveness of surgical procedures, such as thyroidectomy and nutraceutical treatments, are accompanied by several difficulties and still require further research. Alternatively, the DNA-damaging traditional model of chemotherapy is linked to poor solubility, untoward systemic effects, and associated cytotoxicity, instituting an urgent need to establish a specialized, factual, and reliable delivery tool. In order to overcome the limitations of conventional delivery systems, nanotechnology-based delivery tools have shown the potential of articulating endless inherent implementations. The probable benefits of emerging nanotechnology-based diagnostic techniques include rapid screening and early illness diagnosis, which draws investigators to investigate and assess the possibility of this treatment for TC. Subsequently, organic (e.g., liposomes, polymer-based, and dendrimers) and inorganic (e.g., gold, carbon-based, mesoporous silica, magnetic, and quantum dots) NPs and hybrids thereof (liposome-silica, chitosan-carbon, and cell membrane-coated) have been projected for TC biomarker screening, therapy, and detection, providing better outcomes than traditional diagnostic and treatment techniques. Therefore, this review aims to offer a broad perspective on nanoplatform in TC, accompanied by present and potential future treatment options and screening techniques. The goal of cancer therapy has traditionally been to "search a thorn in a hayloft"; therefore, this article raises the possibility of treating TC using nano-oncotherapeutics, which might be useful clinically and will encourage future researchers to explore this tool's potential and drawbacks.

Biomacromolecule-based nanocarrier strategies to deliver plant-derived bioactive components for cancer treatment: A recent review.

The quest for safe chemotherapy has attracted researchers to explore anticancer potential of herbal medicines. Owing to upsurging evidence of herbal drug's beneficial effects, hopes are restored for augmenting survival rates in cancer patients. However, phytoconstituents confronted severe limitations in terms of poor absorption, low-stability, and low bioavailability. Along with toxicity issues associated with phytoconstituents, quality control and limited regulatory guidance also hinder the prevalence of herbal medicines for cancer therapy. Attempts are underway to exploit nanocarriers to circumvent the limitations of existing and new herbal drugs, where biological macromolecules (e.g., chitosan, hyaluronic acid, etc.) are established highly effective in fabricating nanocarriers and cancer targeting. Among the discussed nanocarriers, liposomes and micelles possess properties to cargo hydro- and lipophilic herbal constituents with surface modification for targeted delivery. Majorly, PEG, transferrin and folate are utilized for surface modification to improve bioavailability, circulation time and targetability. The dendrimer and carbon nanotubes responded in high-loading efficiency of phytoconstituent; whereas, SLN and nanoemulsions are suited carriers for lipophilic extracts. This review emphasized unveiling the latent potential of herbal drugs along with discussing on extended benefits of nanocarriers-based delivery of phytoconstituents for safe cancer therapy owing to enhanced clinical and preclinical outcomes without compromising safety.

Study on Sulfamethoxazole-Piperazine Salt: A Mechanistic Insight into Simultaneous Improvement of Physicochemical Properties.

Multidrug salts represent more than one drug in a crystal lattice and thus could be used to deliver multiple drugs in a single dose. It showcases unique physicochemical properties in comparison to individual components, which could lead to improved efficacy and therapeutic synergism. This study presents the preparation and scale-up of sulfamethoxazole-piperazine salt, which has been thoroughly characterized by X-ray diffraction and thermal and spectroscopic analyses. A detailed mechanistic study investigates the impact of piperazine on the microenvironmental pH of the salt and its effect on the speciation profile, solubility, dissolution, and diffusion profile. Also, the improvement in the physicochemical properties of sulfamethoxazole due to the formation of salt was explored with lattice energy contributions. A greater ionization of sulfamethoxazole (due to pH changes contributed by piperazine) and lesser lattice energy of sulfamethoxazole-piperazine contributed to improved solubility, dissolution, and permeability. Moreover, the prepared salt addresses the stability issues of piperazine and exhibits good stability behavior under accelerated stability conditions. Due to the improvement of physicochemical properties, the sulfamethoxazole-piperazine salt demonstrates better pharmacokinetic parameters in comparison to sulfamethoxazole and provides a strong suggestion for the reduction of dose. The following study suggests that multidrug salts can concurrently enhance the physicochemical properties of drugs and present themselves as improved fixed-dose combinations.

Recent progress of targeted nanocarriers in diagnostic, therapeutic, and theranostic applications in colorectal cancer.

Cancer at the lower end of the digestive tract, colorectal cancer (CRC), starts with asymptomatic polyps, which can be diagnosed as cancer at a later stage. It is the fourth leading cause of malignancy-associated mortality worldwide. Despite progress in conventional treatment strategies, the possibility to overcome the mortality and morbidity issues with the enhancement of the lifespan of CRC patients is limited. With the advent of nanocarrier-based drug delivery systems, a promising revolution has been made in diagnosis, treatment, and theranostic purposes for cancer management. Herein, we reviewed the progress of miniaturized nanocarriers, such as liposomes, niosomes, solid lipid nanoparticles, micelles, and polymeric nanoparticles, employed in passive and active targeting and their role in theranostic applications in CRC. With this novel scope, the diagnosis and treatment of CRC have proceeded to the forefront of innovation, where specific characteristics of the nanocarriers, such as processability, flexibility in developing precise architecture, improved circulation, site-specific delivery, and rapid response, facilitate the management of cancer patients. Furthermore, surface-engineered technologies for the nanocarriers could involve receptor-mediated deliveries towards the overexpressed receptors on the CRC microenvironment. Moreover, the potential of clinical translation of these targeted miniaturized formulations as well as the possible limitations and barriers that could impact this translation into clinical practice were highlighted. The advancement of these newest developments in clinical research and progress into the commercialization stage gives hope for a better tomorrow.

Miniaturized Polymeric Systems for the Intravaginal Gene Therapies: Recent Update on Unconventional Delivery.

The prevalence of vaginal infection is increasing among women, especially at reproductive age. For proper eradication of infection, the effective concentration of a drug is required at the infection site. Therefore, local delivery is recommended to exert a direct therapeutic effect at the site action that causes a reduction in dose and side effects. The main focus of vaginal drug delivery is to enhance retention time and patient compliance. The high recurrence rate of vaginal infection due to the lack of effective treatment strategies opens the door for new therapeutic approaches. To combat these setbacks, intravaginal gene therapies have been investigated. High attention has been gained by vaginal gene therapy, especially for sexually transmitted infection treatment. Despite much research, no product is available in the market, although in vitro and preclinical data support the vaginal route as an effective route for gene administration. The main focus of this review is to discuss the recent advancement in miniaturized polymeric systems for intravaginal gene therapies to treat local infections. An overview of different barriers to vaginal delivery and challenges of vaginal infection treatment are also summarised.

Ayurveda-based phytochemical composition attenuates lung inflammation and precipitates pharmacokinetic interaction with favipiravir: an in vivo investigation using disease-state of acute lung injury.

Acute respiratory distress syndrome (ARDS) is a critical form of acute lung injury (ALI). Here, we investigated the effect of a defined combination of ten pure phytochemicals in equal proportions of weight (NPM) from plants, recommended by Ayurveda for any protective action against lipopolysaccharide (LPS)-induced ALI. Results indicate that NPM markedly improved protein and neutrophil contents, myeloperoxidase and hydroxyproline levels, oxidative stress markers (glutathione and malonaldehyde), inflammatory cytokines, and genes (IL-6, TNF-α, TGF-ß, and NF-κB/IκBα) in BALF/lung tissue. The histopathological examination of the lung revealed the shielding effect of NPM against ALI. NPM exhibited a protective effect on the lung by reducing oxidative stress and inhibiting inflammation. A substantial drop in favipiravir's oral exposure was observed in ALI-state compared to normal-state, but oral exposure upon NPM treatment in ALI-state followed similar behaviour of favipiravir alike normal-state without NPM treatment. Overall, results offer potential insight into Ayurvedic recommendations for immunity boosting during ALI situations.

Stimuli-Responsive in situ Spray Gel of Miconazole Nitrate for Vaginal Candidiasis.

Vaginal candidiasis is a common form of infection in women caused by Candida species. Due to several drawbacks of conventional treatments, the current research is attempted to formulate and optimize a miconazole nitrate-loaded in situ spray gel for vaginal candidiasis. The stimuli-responsive (pH and thermo-responsive) polymers selected for the in situ gel were chitosan and poloxamer 407, respectively, whereas hydroxypropyl methylcellulose (HPMC) was introduced in the formulation to further improve the mucoadhesive property. The dispersion of each polymer was carried out using the cold method, whereas the optimization of the formulation was achieved using Box-Behnken statistical design considering viscosity and gelation temperature as dependent variables. Present design achieved the optimized outcome with HPMC, poloxamer and chitosan at 0.52% (w/v), 18.68% (w/v) and 0.41% (w/v), respectively. Evaluation of drug-excipients compatibility was performed using differential scanning calorimetry, Fourier transform infrared spectroscopy, and thermogravimetric analysis where the results showed the absence of any chemical interaction between the polymers and drug component. The optimized formulation showed gelation temperature at 31°C allowing in situ phase transition in a vaginal environment; pH of 4.21 is suitable for use in the vaginal cavity, and appropriate viscosity (290 cP) at storage temperature (below 30°C) would allow spraying at ease, whereas strong mucoadhesive force (22.4±0.513 g) would prevent leaking of the formulation after application. The drug release profile showed sustained release up to 24 h with a cumulative drug release of 81.72%, which is significantly better than the marketed miconazole nitrate cream. In addition, an improved antifungal activity could be correlated to the sustained release of the drug from the formulation. Finally, the safety of the formulation was established while tested on HaCaT cell lines. Based on our findings, it could be concluded that the in situ hydrogel formulation using stimuli-responsive polymers could be a viable alternative to the conventional dosage form that can help to reduce the frequency of administration with ease of application to the site of infection, thus will provide better patient compliance.

Nose-to-brain delivery of octreotide acetate in situ gel for pituitary adenoma: Pharmacological and in vitro cytotoxicity studies.

Octreotide acetate (OA), a potent octapeptide, is used in the treatment of pituitary adenoma. An approach has been made in the present research to formulate an OA-loaded intranasal in situ gel (OA-ISG) to target pituitary adenoma. To achieve the objective of the present work, OA-ISG was fabricated using cold method, and further optimization was done by 32 factorial design. The optimized formulation was evaluated for gelation temperature, mucoadhesive strength, and % drug release (8 h), and the results were found to be 30.01 ± 0.4 °C, 40.12 ± 0.5 g, and 98.54 ± 0.45 %, respectively. Brain availability of OA was determined through gamma scintigraphy, wherein Cmax for technetium (99mTC) labeled intranasal OA-ISG (99mTC-OA-ISG) was found to be 1.041 % RA/g, and the findings for 99mTC-OA-Solution (intranasal) and 99mTC-OA-Solution (intravenous) were 0.395 % and 0.164 % RA/g, respectively. Consequently, a 3-10-fold increase in brain OA concentrations was observed upon intranasal administration (OA-ISG) as compared to others. Additionally, drug targeting index (100.13), targeting efficiency (10013 %), and direct transport percentage (2564.1 %) corroborate brain targeting of OA via intranasal route. Further, the cytotoxic potential of OA-ISG was screened on human pituitary tumor (GH3) cell lines using MTT assay. The IC50 value was found to be 9.5 µg/mL for OA-ISG, whereas it was 20.1 µg/mL for OA-Solution, thereby confirming the superior results of OA-ISG as compared to OA-Solution. Hence, the developed intranasal OA-ISG can be further explored for establishing its potential clinical safety, and as effective platform for targeted drug delivery to the brain in pituitary adenoma.

Tocotrienol in the Treatment of Topical Wounds: Recent Updates.

Healing wounds is an important attempt to keep the internal higher organs safe. Complications in topical wound healing may lead to the formation of scars, which can affect the patient's quality of life. Although several approaches are ongoing in parallel in the exploration of natural compounds via advanced delivery, in this article, an attempt has been made to highlight tocotrienol. Tocotrienol is a natural form of vitamin E and has shown its potential in certain pharmacological activities better than tocopherol. Its antioxidant, anti-inflammatory, cell signal-mediating effects, angiogenic properties, management of scar, and promotion of wound environment with essential factors have shown potential in the management of topical wound healing. Therefore, this review has aimed to focus on recent advances in topical wound healing through the application of tocotrienols. Challenges in delivering tocotrienols to the topical wound due to its large molecular weight and higher logP have also been explored using nanotechnological-based carriers, which has made tocotrienol a potential tool to facilitate the closure of wounds. Exploration of tocotrienol has also been made in human volunteers for biopsy wounds; however, the results are yet to be reported. Overall, based on the current findings in the literature, it could be inferred that tocotrienol would be a viable alternative to the existing wound dressing components for the management of topical wounds.

Recent developments in plant-derived edible nanoparticles as therapeutic nanomedicines.

The use of nanotechnology in the treatment of numerous disorders has proven effective. The predicted development of plant-derived edible nanoparticles (PDNPs) as potential therapeutic agents for treating illness or in the delivery of drugs is inevitable. PDNPs generated from plants resemble mammal-extracted exosomes structurally. In contrast to their excellent biocompatibility with healthy cells, PDNPs are skewed toward malignancies by selectively targeting those cells via unique endocytic pathways. They can be generated in large quantities, are nontoxic, and have tissue-specific targeting abilities. Thus, with fewer off-target effects, using these PDNPs could broaden the breadth of pharmacological therapy. In this discussion, we emphasize the properties and biological activities of PDNPs isolated from fruits and vegetables and discuss the promising implications of these particles as nanomedicines. PRACTICAL APPLICATIONS: PDNPs have reportedly been employed for therapeutic applications for several ailments and are believed to have characteristics in common with exosomes generated from mammals. The advantages of PDNPs over mammalian-derived exosomes are numerous. Firstly, they may be produced on a commercial scale using a variety of efficient renewable sources. Secondly, the PDNPs' natural components developed in plant cells promise improved cytocompatibility, tolerability, low cytotoxicity, or other adverse effects. We evaluated some current studies on the applications and potential of PDNPs in this article. PDNPs could create new opportunities for drug discovery because of recent advancements in medicine and drug delivery system nanotechnology. Unfortunately, the precise mechanisms behind PDNP's functions and interaction in pathogenic processes have not yet been completely elucidated; as a result, the potential consequences of their clinical use are uncertain. Overall, PDNPs show a wide range of therapeutic possibilities that may be advantageous to patients and might eventually make up the next generation of pharmaceuticals.

Dendrimer-based delivery of macromolecules for the treatment of brain tumor.

Brain tumor represents the most lethal form of cancer with the highest mortality and morbidity rates irrespective of age and sex. Advancements in macromolecule-based therapy (such as nucleic acids and peptides) have shown promising roles in the treatment of brain tumor where the phenomenon of severe toxicities due to the conventional chemotherapeutic agents can be circumvented. Despite its preclinical progress, successful targeting of these macromolecules across the blood-brain barrier without altering their physical and chemical characteristics is of great challenge. With the advent of nanotechnology, nowadays targeted delivery of therapeutics is being explored extensively and these macromolecules, including peptides and nucleic acids, have shown initial success in the treatment, where dendrimer has shown its potential for optimal delivery. Dendrimers are being favored as a mode of drug delivery due to their nano-spherical size and structure, high solubilization potential, multivalent surface, and high loading capacity, where biomolecule resembling characteristics of dendritic 3D structures has shown effective delivery of various therapeutic agents to the brain. Armed with targeting ligands to these dendrimers further expedite the transportation of these multifunctional shuttles specifically to the glioblastoma cells. Thus, a focus has been made in this review on therapeutic applications of dendrimer platforms in brain tumor treatment. The future development of dendrimers as a potential platform for nucleic acid and peptide delivery and its promising clinical application could provide effective and target-specific treatment against brain tumors.

Nanocarrier-based co-delivery approaches of chemotherapeutics with natural P-glycoprotein inhibitors in the improvement of multidrug resistance cancer therapy.

Chemotherapy is the mainstay in cancer treatment; however, its application is clinically limited to patients with multidrug resistance (MDR). MDR reverses the role of chemotherapy through significant attribution to pharmacokinetic characteristics, where ATP-binding cassette transporter proteins, P-glycoprotein (P-gp), pump out the intracellularly transported chemotherapeutics from the cancer cells. Therefore, overexpression of such receptors on MDR cancer cell surfaces tends to decrease the efficacy of a large number of existing chemotherapeutics. P-gp inhibitors, especially of natural origin, play a vital role in enhancing the cellular concentration of clinically applicable chemotherapeutics. Therefore, co-administration of these natural P-gp inhibitors with chemotherapeutics could improve chemotherapeutic efficacy against MDR cancer, which has been evidenced in the literature. Co-delivery of these therapeutic components can effectively be made using the emerging nanotechnology platform, which could facilitate controlled delivery of the incorporated components to the cancerous microenvironment, through passive and active targeting. Thereby, cellular retention of chemotherapeutic agents by the P-gp mediated inhibitory effect on the efflux pump using the nanocarrier co-delivery platform could improve the anticancer potential of the chemotherapeutics. This review has presented the advancement of naturally occurring P-gp inhibitors as a promising adjuvant in chemotherapy to modulate the pharmacokinetic properties of chemotherapeutic agents using the nanotechnology platform.

Mucoadhesive Nanocarriers as a Promising Strategy to Enhance Intracellular Delivery against Oral Cavity Carcinoma.

Oral cancer, particularly squamous cell carcinoma (SCC), has posed a grave challenge to global health due to its high incidence, metastasis, and mortality rates. Despite numerous studies and favorable improvements in the therapeutic strategies over the past few decades, the prognosis of this disease remains dismal. Moreover, several drawbacks are associated with the conventional treatment; including permanent disfigurement and physical impairment that are attributed to surgical intervention, and systemic toxicity that results from aggressive radio- or chemotherapies, which impacts patients' prognosis and post-treatment quality of life. The highly vascularized, non-keratinized oral mucosa appears as a potential route for cytotoxic drug administration in treating oral cancer. It acts as a non-invasive portal for drug entry targeting the local oral lesions of the early stages of cancer and the systemic metastasis sites of advanced cancer. The absorption of the poorly aqueous-soluble anti-cancer drugs can be enhanced due to the increased permeability of the ulcerous mucosa lining in the disease state and by bypassing the hepatic first-pass metabolism. However, some challenges in oral transmucosal drug delivery include the drugs' taste, the limited surface area of the membrane lining the oral cavity, and flushing and enzymatic degradation by saliva. Therefore, mucoadhesive nanocarriers have emerged as promising platforms for controlled, targeted drug delivery in the oral cavity. The surface functionalization of nanocarriers with various moieties allows for drug targeting, bioavailability enhancement, and biodistribution at the site of action, while the mucoadhesive feature prolongs the drug's residence time for preferential accumulation to optimize the therapeutic effect and reduce systemic toxicity. This review has been focused to highlight the potential of various nanocarriers (e.g., nanoparticles, nanoemulsions, nanocapsules, and liposomes) in conferring targeting, solubility and bioavailability enhancement of actives and mucoadhesive properties as novel tumor-targeted drug delivery approaches in oral cancer treatment.