Cell-Penetrating Peptides as Keys to Endosomal Escape and Intracellular Trafficking in Nanomedicine Delivery.

This review article discusses the challenges of delivering cargoes to the cytoplasm, for example, proteins, peptides, and nucleic acids, and the mechanisms involved in endosomal escape. Endocytosis, endosomal maturation, and exocytosis pose significant barriers to effective cytoplasmic delivery. The article explores various endosomal escape mechanisms, such as the proton sponge effect, osmotic lysis, membrane fusion, pore formation, membrane destabilization/ disruption, and vesicle budding and collapse. Additionally, it discusses the role of lysosomes, glycocalyx, and molecular crowding in the cytoplasmic delivery process. Despite the recent advances in nonviral delivery systems, there is still a need to improve cytoplasmic delivery. Strategies such as fusogenic peptides, endosomolytic polymers, and cell-penetrating peptides have shown promise in improving endosomal escape and cytoplasmic delivery. More research is needed to refine these strategies and make them safer and more effective. In conclusion, the article highlights the challenges associated with cytoplasmic delivery and the importance of understanding the mechanisms involved in endosomal escape. A better understanding of these processes could result in the creation of greater effectiveness and safe delivery systems for various cargoes, including proteins, peptides, and nucleic acids.

Leveraging hypoxia in triple-negative breast cancer as a promising treatment strategy.

Current treatment strategies for triple-negative breast cancer (TNBC) are based upon conventional chemotherapy, immunotherapy, or a combination of both. The treatment regimen for chemotherapy is often a combination of two or more drugs, either dose dense or low dose for synergy. Anthracyclines, alkylating agents, antimicrotubule agents, and antimetabolites for early-stage TNBC; and antimetabolites, non-taxane microtubule inhibitors, and cross-linker platinums for late-stage TNBC are usually administered in the clinical setting. Newer options for patients with advanced TNBC, such as poly (ADP-ribose) polymerase (PARP) inhibitors and immune checkpoint inhibitors, have recently emerged for cases where surgery is not a viable option and the disease has metastasized. This review outlines the current trends in hypoxia-inspired treatment strategies for TNBC with a focus on clinical trials.

Multiple Protein Biomarkers and Different Treatment Strategies for Colorectal Carcinoma: A Comprehensive Prospective.

In this review, we emphasized important biomarkers, pathogenesis, and newly developed therapeutic approaches in the treatment of colorectal cancer (CRC). This includes a complete description of small-molecule inhibitors, phytopharmaceuticals with antiproliferative potential, monoclonal antibodies for targeted therapy, vaccinations as immunotherapeutic agents, and many innovative strategies to intervene in the interaction of oncogenic proteins. Many factors combine to determine the clinical behavior of colorectal cancer and it is still difficult to comprehend the molecular causes of a person's vulnerability to CRC. It is also challenging to identify the causes of the tumor's onset, progression, and responsiveness or resistance to antitumor treatment. Current recommendations for targeted medications are being updated by guidelines throughout the world in light of the growing number of high-quality clinical studies. So, being concerned about the aforementioned aspects, we have tried to present a summarized pathogenic view, including a brief description of biomarkers and an update of compounds with their underlying mechanisms that are currently under various stages of clinical testing. This will help to identify gaps or shortfalls that can be addressed in upcoming colorectal cancer research.

Curcumin and its Derivatives Targeting Multiple Signaling Pathways to Elicit Anticancer Activity: A Comprehensive Perspective.

The uncontrolled growth and spread of aberrant cells characterize the group of disorders known as cancer. According to GLOBOCAN 2022 analysis of cancer patients in either developed countries or developing countries the main concern cancers are breast cancer, lung cancer, and liver cancer which may rise eventually. Natural substances with dietary origins have gained interest for their low toxicity, anti-inflammatory, and antioxidant effects. The evaluation of dietary natural products as chemopreventive and therapeutic agents, the identification, characterization, and synthesis of their active components, as well as the enhancement of their delivery and bioavailability, have all received significant attention. Thus, the treatment strategy for concerning cancers must be significantly evaluated and may include the use of phytochemicals in daily lifestyle. In the present perspective, we discussed one of the potent phytochemicals, that has been used over the past few decades known as curcumin as a panacea drug of the "Cure-all" therapy concept. In our review firstly we included exhausted data from in-vivo and in-vitro studies on breast cancer, lung cancer, and liver cancer which act through various cancer-targeting pathways at the molecular level. Now, the second is the active constituent of turmeric known as curcumin and its derivatives are enlisted with their targeted protein in the molecular docking studies, which help the researchers design and synthesize new curcumin derivatives with respective implicated molecular and cellular activity. However, curcumin and its substituted derivatives still need to be investigated with unknown targeting mechanism studies in depth.

Structural Insights into N-heterocyclic Moieties as an Anticancer Agent against Hepatocellular Carcinoma: An Exhaustive Perspective.

Hepatocellular carcinoma (HCC) is rapidly spreading around the world with a high mortality rate. In the low- and middle-income nations most impacted by HCV and HBV infections, HCC places a significant strain on the healthcare system and leaches productive capability. An extensive study on HCC to create novel therapeutic approaches was motivated by the lack of adequate preventive or curative therapy methods. Several medications have been put forward and some drug molecules are under investigation by the Food and Drug Administration (FDA) for the treatment of HCC. However, these therapeutic choices fall short of the ideal due to toxicity and the rapid rise in drug resistance which decreases the efficacy of these therapeutics and leads to the severity of hepatocellular carcinoma. Therefore, concerning these problems, there is a critical need for novel systemic combination therapies as well as novel molecular entities that target various signalling pathways, reducing the likelihood that cancer cells may develop treatment resistance. In this review, we discuss the conclusions of several studies suggesting that the N-heterocyclic ring system is a key structural component of many synthetic drugs with a diverse range of biological activities. Following nuclei, such as pyridazine, pyridine, and pyrimidines, along with benzimidazole, indole, acridine, oxadiazole, imidazole, isoxazole, pyrazole, quinolines, and quinazolines, have been included to provide a general overview of the link between structure and activity between heterocyclics and their derivatives against hepatocellular carcinoma. A comprehensive investigation of the structure-activity relationship between the series may be done by the direct comparison of anticancer activities with the reference.

Structural Insight on GPR119 Agonist as Potential Therapy for Type II Diabetes: A Comprehensive Review.

Diabetes Mellitus (DM) is a long-term metabolic condition that is characterized by excessive blood glucose. DM is the third most death-causing disease, leading to retinopathy, nephropathy, loss of vision, stroke, and cardiac arrest. Around 90% of the total cases of diabetic patients have Type II Diabetes Mellitus (T2DM). Among various approaches for the treatment of T2DM. G proteincoupled receptors (GPCRs) 119 have been identified as a new pharmacological target. GPR119 is distributed preferentially in the pancreas ß-cells and gastrointestinal tract (enteroendocrine cells) in humans. GPR119 receptor activation elevates the release of incretin hormones such as Glucagon-Like Peptide (GLP1) and Glucose Dependent Insulinotropic Polypeptide (GIP) from intestinal K and L cells. GPR119 receptor agonists stimulate intracellular cAMP production via Gαs coupling to adenylate cyclase. GPR119 has been linked to the control of insulin release by pancreatic ß-cells, as well as the generation of GLP-1 by enteroendocrine cells in the gut, as per in vitro assays. The dual role of the GPR119 receptor agonist in the treatment of T2DM leads to the development of a novel prospective anti-diabetic drug and is thought to have decreased the probability of inducing hypoglycemia. GPR119 receptor agonists exert their effects in one of two ways: either by promoting glucose absorption by ß-cells, or by inhibiting α-cells' ability to produce glucose. In this review, we summarized potential targets for the treatment of T2DM with special reference to GPR119 along with its pharmacological effects, several endogenous as well as exogenous agonists, and its pyrimidine nucleus containing synthetic ligands.

Nanomedicine approaches to reduce cytokine storms in severe infections.

During a cytokine storm, dysregulated proinflammatory cytokines are produced in excess. Cytokine storms occur in multiple infectious diseases, including Coronavirus 2019 (COVID-19). Thus, eliminating cytokine storms to enhance patient outcomes is crucial. Given the numerous cytokines involved, individual therapies might have little effect. Traditional cytokines might be less effective than medicines that target malfunctioning macrophages. Nanomedicine-based therapeutics reduce cytokine production in animal models of proinflammatory illnesses. The unique physicochemical features and controlled nano-bio interactions of nanotechnology show promise in healthcare and could be used to treat several stages of this virus-induced sickness, including cytokine storm mortality. Macrophage-oriented nanomedicines can minimize cytokine storms and associated harmful effects, enhancing patient outcomes. Here, we also discuss engineering possibilities for enhancing macrophage efficacy with nanodrug carriers.

Comparison of Tau and Amyloid-ß Targeted Immunotherapy Nanoparticles for Alzheimer's Disease.

Alzheimer's disease (AD) is a rapidly growing global concern associated with the accumulation of amyloid-ß plaques and intracellular neurofibrillary tangles in the brain combined with a high acetylcholinesterase activity. AD diagnosis is usually made too late, when patients have an extensive neuronal death, and brain damage is irreversible. Several therapeutic targets have been defined mainly related to two hypotheses of AD: the tau hypothesis and the amyloid-ß hypothesis. Here, we intend to investigate and to compare different therapeutic approaches for AD, mainly based on nanoparticles (NPs) targeted at the brain and at the pathological hallmarks of the disease. We analyzed preclinical trials that have successfully improved drug bioavailability in the brain by using targeted nanocarriers towards either tau, amyloid-ß, or both. We then compared these trials to find out which protein is more efficient in therapeutic targeting. We found that the search for a cure was mostly based on the amyloid-ß hypothesis, with Aß dysplasia emerging as the most confirmed and convincing therapeutic target. Targeted NPs have proven useful to enhance both the bioavailability and the performance of therapies against AD in animal models. A better understanding of AD mechanisms will help the successful application of targeted NPs for combined therapies.

Nanomedicine for overcoming therapeutic and diagnostic challenges associated with pancreatic cancer.

Pancreatic cancer is the second leading cause of cancer-related death in the USA. The 5-year survival rate for pancreatic cancer is as low as 10%, making it one of the most deadly cancers. This dismal prognosis is caused, in part, by the lack of early detection and screening options, leading to late-stage detection of the disease, at a point at which chemotherapy is no longer effective. However, nanoparticle (NP) drug delivery systems have increased the efficacy of chemotherapeutics by improving the targeting ability of drugs to the tumor site, while also decreasing the risk of local and systemic toxicity. Such efforts can contribute to the development of early diagnosis and routine screening tests, which will drastically improve the survival rates and prognosis of patients with pancreatic cancer.

Multiple strategies for the treatment of invasive breast carcinoma: A comprehensive prospective.

In this review, we emphasize on evolving therapeutic strategies and advances in the treatment of breast cancer (BC). This includes small-molecule inhibitors under preclinical and clinical investigation, phytoconstituents with antiproliferative potential, targeted therapies as antibodies and antibody-drug conjugates (ADCs), vaccines as immunotherapeutic agents and peptides as a novel approach inhibiting the interaction of oncogenic proteins. We provide an update of molecules under different phases of clinical investigation which aid in the identification of loopholes or shortcomings that can be overcomed with future breast cancer research.

Nano-therapeutic strategies to target coronavirus.

The coronaviruses have caused severe acute respiratory syndrome (SARS), the Middle East respiratory syndrome (MERS), and the more recent coronavirus pneumonia (COVID-19). The global COVID-19 pandemic requires urgent action to develop anti-virals, new therapeutics, and vaccines. In this review, we discuss potential therapeutics including human recombinant ACE2 soluble, inflammatory cytokine inhibitors, and direct anti-viral agents such as remdesivir and favipiravir, to limit their fatality. We also discuss the structure of the SARS-CoV-2, which is crucial to the timely development of therapeutics, and previous attempts to generate vaccines against SARS-CoV and MERS-CoV. Finally, we provide an overview of the role of nanotechnology in the development of therapeutics as well as in the diagnosis of the infection. This information is key for computational modeling and nanomedicine-based new therapeutics by counteracting the variable proteins in the virus. Further, we also try to effectively share the latest information about many different aspects of COVID-19 vaccine developments and possible management to further scientific endeavors.

Folate Functionalized Lipid Nanoparticles for Targeted Therapy of Methicillin-Resistant Staphylococcus aureus.

Methicillin-resistant Staphylococcus aureus (MRSA), commonly called a superbug, is a highly alarming antibiotic-resistant population of Staphylococcus aureus (S. aureus) bacteria. Vancomycin (VAN) was first approved by the FDA in 1988, and it is still regarded as the treatment of choice for MRSA. The efficacy of VAN treatment has become less effective due to the development of VAN resistance in MRSA and the potential for nephrotoxicity. This study aims to improve the efficacy of VAN treatment by identifying the folate receptor for MRSA infected tissues and developing folate decorated lipid nanoparticles containing VAN (LVAN). In comparison to conventional VAN, LVAN showed a higher bactericidal effect and a superior ability to inhibit biofilm in MRSA with an enhanced accumulation in MRSA infected thigh tissues and a reduced accumulation in kidney. The results suggested that LVAN is a promising candidate to overcome the current limitations of bacterial resistance and adverse side effects in kidneys found in VAN.

Overcoming the Tumor Microenvironmental Barriers of Pancreatic Ductal Adenocarcinomas for Achieving Better Treatment Outcomes.

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive disease with the lowest survival rate among all solid tumors. The lethality of PDAC arises from late detection and propensity of the tumor to metastasize and develop resistance against chemo and radiation therapy. A highly complex tumor microenvironment composed of dense stroma, immune cells, fibroblast, and disorganized blood vessels, is the main obstacle to current PDAC therapy. Despite the tremendous success of immune checkpoint inhibitors (ICIs) in cancers, PDAC remains one of the poorest responders of ICIs therapy. The immunologically "cold" phenotype of PDAC is attributed to the low mutational burden, high infiltration of myeloid-derived suppressor cells and T-regs, contributing to a significant immunotherapy resistance mechanism. Thus, the development of innovative strategies for turning immunologically "cold" tumor into "hot" ones is an unmet need to improve the outcome of PDAC ICIs therapies. Other smart strategies, such as nanomedicines, sonic Hedgehog inhibitor, or smoothened inhibitor, are discussed to enhance chemotherapeutic agents' efficiency by disrupting the PDAC stroma. This review highlights the current challenges and various preclinical and clinical strategies to overcome current PDAC therapy difficulties, thus significantly advancing PDAC research knowledge.

Transferrin: Biology and Use in Receptor-Targeted Nanotherapy of Gliomas.

Gliomas constitute 80% of malignant brain tumors. The survival rate of patients diagnosed with malignant gliomas is only 34.4%, as seen in both adults as well as children. The biggest challenge in treatment of gliomas is the impenetrable blood-brain barrier. With the availability of only a very few choices of chemotherapeutics in the treatment of gliomas, it is imperative that a novel strategy to effectively deliver drugs into the brain is researched and applied. The most popular strategy that is gaining importance is the receptor-mediated uptake of targeted nanoparticles comprising of ligands specific to the receptors. This review discusses briefly one such receptor called the transferrin receptor that is highly expressed in the brain and can be applied effectively for targeted nanoparticle delivery systems in gliomas.

Recent advances in nano delivery systems for blood-brain barrier (BBB) penetration and targeting of brain tumors.

Gliomas constitute about 80% of brain tumors and have a meager two-year survival rate. The treatment options available are very few because of poor prognosis and a lack of targeted nanodelivery systems that can cross the blood-brain barrier (BBB) and the blood-tumor barrier. This short review attempts to clarify the challenges for delivery systems designed to cross the BBB, and provides a brief description of the different types of targeted nanodelivery system that have shown potential for success in delivering drugs to the brain. Further, this review describes the most recent studies that have developed nanoparticles for brain delivery in the past five years. We also provide an insight into the most recent clinical trials designed to assess the efficacy of these nanodelivery systems for glioma.

CD44 Targeted Nanomaterials for Treatment of Triple-Negative Breast Cancer.

Identified as the second leading cause of cancer-related deaths among American women after lung cancer, breast cancer of all types has been the focus of numerous research studies. Even though triple-negative breast cancer (TNBC) represents 15-20% of the number of breast cancer cases worldwide, its existing therapeutic options are fairly limited. Due to the pivotal role of the presence/absence of specific receptors to luminal A, luminal B, HER-2+, and TNBC in the molecular classification of breast cancer, the lack of these receptors has accounted for the aforementioned limitation. Thereupon, in an attempt to participate in the ongoing research endeavors to overcome such a limitation, the conducted study adopts a combination strategy as a therapeutic paradigm for TNBC, which has proven notable results with respect to both: improving patient outcomes and survivability rates. The study hinges upon an investigation of a promising NPs platform for CD44 mediated theranostic that can be combined with JAK/STAT inhibitors for the treatment of TNBC. The ability of momelotinib (MMB), which is a JAK/STAT inhibitor, to sensitize the TNBC to apoptosis inducer (CFM-4.16) has been evaluated in MDA-MB-231 and MDA-MB-468. MMB + CFM-4.16 combination with a combination index (CI) ≤0.5, has been selected for in vitro and in vivo studies. MMB has been combined with CD44 directed polymeric nanoparticles (PNPs) loaded with CFM-4.16, namely CD44-T-PNPs, which selectively delivered the payload to CD44 overexpressing TNBC with a significant decrease in cell viability associated with a high dose reduction index (DRI). The mechanism underlying their synergism is based on the simultaneous downregulation of P-STAT3 and the up-regulation of CARP-1, which has induced ROS-dependent apoptosis leading to caspase 3/7 elevation, cell shrinkage, DNA damage, and suppressed migration. CD44-T-PNPs showed a remarkable cellular internalization, demonstrated by uptake of a Rhodamine B dye in vitro and S0456 (NIR dye) in vivo. S0456 was conjugated to PNPs to form CD44-T-PNPs/S0456 that simultaneously delivered CFM-4.16 and S0456 parenterally with selective tumor targeting, prolonged circulation, minimized off-target distribution.

LDL receptors and their role in targeted therapy for glioma: a review.

Gliomas are highly lethal forms of cancers occurring in the brain. Delivering the drugs into the brain is a major challenge to the treatment of gliomas because of the highly selectively permeable blood-brain barrier (BBB). Tapping the potential of receptor-mediated drug delivery systems using targeted nanoparticles (NPs) is a sought-after step forward toward successful glioma treatment. Several receptors are the focus of research for application in drug delivery. Low-density lipoprotein receptors (LDLR) are abundantly expressed in both healthy brains and diseased brains with a disrupted BBB. In this review, we discuss the LDLR and the types of NPs that have been used to target the brain via this receptor.

Folate Receptors' Expression in Gliomas May Possess Potential Nanoparticle-Based Drug Delivery Opportunities.

Brain cancer effected around estimated 23 890 adults and 3540 children under the age of 15 in 2020. The chemotherapeutic agents that are already approved by the FDA for brain cancer are proving to be not highly effective because of the interference from the tumor microenvironment as well as their own toxicities. Added to this is the impedance presented by the extremely restrictive permeability of the blood brain barrier (BBB). Targeted nanoparticulate drug delivery systems offer a good opportunity to traverse the BBB and selectively target the tumor cells. Folate receptors are found to be one of the most useful targets for drug delivery to the brain. Hence, this Mini-Review discusses the folate receptors and their application in the treatment of brain cancers using targeted nanoparticles.

Novel approaches for the treatment of methicillin-resistant Staphylococcus aureus: Using nanoparticles to overcome multidrug resistance.

Methicillin-resistant Staphylococcus aureus (MRSA) causes serious infections in both community and hospital settings, with high mortality rates. Treatment of MRSA infections is challenging because of the rapidly evolving resistance mechanisms combined with the protective biofilms of S. aureus. Together, these characteristic resistance mechanisms continue to render conventional treatment modalities ineffective. The use of nanoformulations with unique modes of transport across bacterial membranes could be a useful strategy for disease-specific delivery. In this review, we summarize treatment approaches for MRSA, including novel techniques in nanoparticulate designing for better therapeutic outcomes; and facilitate an understanding that nanoparticulate delivery systems could be a robust approach in the successful treatment of MRSA.

Comparing and Contrasting MERS, SARS-CoV, and SARS-CoV-2: Prevention, Transmission, Management, and Vaccine Development.

The COVID-19 pandemic is responsible for an unprecedented disruption to the healthcare systems and economies of countries around the world. Developing novel therapeutics and a vaccine against SARS-CoV-2 requires an understanding of the similarities and differences between the various human coronaviruses with regards to their phylogenic relationships, transmission, and management. Phylogenetic analysis indicates that humans were first infected with SARS-CoV-2 in late 2019 and the virus rapidly spread from the outbreak epicenter in Wuhan, China to various parts of the world. Multiple variants of SARS-CoV-2 have now been identified in particular regions. It is apparent that MERS, SARS-CoV, and SARS-CoV-2 present with several common symptoms including fever, cough, and dyspnea in mild cases, but can also progress to pneumonia and acute respiratory distress syndrome. Understanding the molecular steps leading to SARS-CoV-2 entry into cells and the viral replication cycle can illuminate crucial targets for testing several potential therapeutics. Genomic and structural details of SARS-CoV-2 and previous attempts to generate vaccines against SARS-CoV and MERS have provided vaccine targets to manage future outbreaks more effectively. The coordinated global response against this emerging infectious disease is unique and has helped address the need for urgent therapeutics and vaccines in a remarkably short time.