Emerging pro-drug and nano-drug strategies for gemcitabine-based cancer therapy

Gemcitabine has been extensively applied in treating various solid tumors. Nonetheless,the clinical performance of gemcitabine is severely restricted by its unsatisfactory pharmacokinetic parameters and easy deactivation mainly because of its rapid deamination, deficiencies in deoxycytidine kinase (DCK), and alterations in nucleoside transporter. On this account, repeated injections with a high concentration of gemcitabine are adopted, leading to severe systemic toxicity to healthy cells. Accordingly, it is highly crucial to fabricate efficient gemcitabine delivery systems to obtain improved therapeutic efficacy of gemcitabine. A large number of gemcitabine pro-drugs were synthesized by chemical modification of gemcitabine to improve its biostability and bioavailability. Besides,gemcitabine-loaded nano-drugs were prepared to improve the delivery efficiency. In this review article, we introduced different strategies for improving the therapeutic performance of gemcitabine by the fabrication of pro-drugs and nano-drugs. We hope this review will provide new insight into the rational design of gemcitabine-based delivery strategies for enhanced cancer therapy.

Perspectives on bone-targeted nano-drug carriers for bone tumor treatment

Bone tumour is one of most common primary cancer which exhibits cancerous osteoblastic differentiation and malignant osteoid in patients.At present,chemotherapy(pre-and post-operative)is used as a standard treatment protocol for bone tumour.However,drugs used in the treatment of bone tumour induce high toxicity to normal tissues including anaemia,neutropenia,thrombocytopenia,and heart damage which further reduce the survival rate of patients.Therefore,there is an urgent need to develop a new therapeutic approach for the treatment such that it induce maximum cell killing effect in tumor cells while sparing the healthy bone cells.In this article,some new perspectives were provided on the development of bone-targeted nano-drug carriers for bone cancer treatment.We hope such discussions wouldencourage more detailed and careful studies to support product development of bone-targeted drug carriers for bone cancer treatment.

Construction of MTX-CS-TMP-NPs Nano-drug Delivery System and its Observation on Telomerase Activity of Cervical Cancer Hela Cells

Objective:To construct methotrexate(MTX)-chitosan(CS)-chuanxiongmuizine(TMP)nano-delivery system MTX-CS-TMP-NPs,and to investigate its effect on the telomerase activity of cervical cancer Hela cells.Methods:MTX-CS and MTX-CS-TMP-NPs were prepared by amide reaction and ionic gel method,and the encapsulation rate and drug loading rate were observed.MTT method and TRAP method were used to detect Hela cells and telomerase activity,and to compare the difference of telomerase activity of MTX,MTX-CS,and MTX-CS-TMP-NPs on cervical cancer Hela cells.Results:In this study,the total amount of TMP was 150μg,of which the amount of free TMP was(26.46±1.72)μg,the encapsulation rate of TMP was(82.36±0.01)%,and the drug loading was(17.62±0.23)mg.The activity of Hela cells increased with the extension of time,and the OD value of Hela cell activity(1.24±0.05)was lower than that of the other three groups at 72 h of treatment,and the difference was statistically significant(P<0.05).The telomerase activity of He La cells in the MTX-CS-TMP-NPs solution treatment group was(0.23±0.12)%lower than that of the other three groups,with statistically significant difference(P<0.05).Conclusion:MTX-CS-TMP-NPs may effectively reduce the activity and telomerase activity of cervical cancer Hela cells,showing its potential anti-cervical cancer effect.

Ultrastructural Findings, at Micrometric and Nanometric Scales, in Rectal and Muscular Mucosa of Patients with HIV/AIDS and Anorectal Pathology

Objective: To determine the ultrastructural findings on Rectal Mucosa (RM) of patients with HIV/AIDS and anorectal pathologies (ARP), at micrometric and nanometric scales. Materials and methods: 5 patients were evaluated, 18 - 55 years old, with ARP (HIV co-infection with HPV, n = 4, and HIV-negative patient with HPV infection) (control n = 1), who were referred to the Coloproctology Unit of the HUC, and subjected to rectoscopy and biopsy. RM samples were identified, placed in a sterile plastic bottle with 1 mL of 2% glutaraldehyde and immediately transported for routine processing of fine cut (60 - 90 nm) to be evaluated via Transmission Electron Microscopy (TEM). They were fixed with Karnovsky solution with Millonig phosphate buffer (pH 7.4 and 320 mOsm) and post-fixed with OsO4 under the same conditions of pH and osmolarity. Results: Ultrastructural findings, at 10&minus;6 scale: 1) Intestinal mucosa: vacuoles of mucus of different sizes that seem to be fused. 2) Smooth muscle cells: loss of definition of contractile myofilaments mass. 3) Unmyelinated axons and terminals of Schwann cells (SC): Edema and loss of their plasma membranes in some areas of association with axon terminals as well as abundant collagen fibers associated with SC. Ultrastructural findings, at 10&minus;9 scale: 1) Smooth muscle cells: folded wrapper cores and edema of mitochondria and rough endoplasmic reticulum cisterns (RER). 2) Myelinated axon terminals: Loss of synaptic vesicles. 3) Fibroblasts: One observes mitochondria and cisterns of RER with alterations. All these alterations can generate intestinal and anorectal dysfunction in these patients. Conclusions: The HIV causes changes in rectal and muscular mucosa despite HAART treatment with undetectable viral load.

Development of nanoscale drug delivery systems of dihydroartemisinin for cancer therapy: A review

Dihydroartemisinin(DHA),a first-line antimalarial drug,has demonstrated great anticancer effects in many types of tumors,including liver cancer,glioblastoma,and pancreatic cancer.Due to its abilities to induce programmed cell death(PCD;apoptosis,autophagy and ferroptosis),inhibit tumor metastasis and angiogenesis,and modulate the tumor microenvironment,DHA could become an antineoplastic agent in the foreseeable future.However,the therapeutic efficacy of DHA is compromised owing to its inherent disadvantages,including poor stability,low aqueous solubility,and short plasma halflife.To overcome these drawbacks,nanoscale drug delivery systems(NDDSs),such as polymeric nanoparticles(NPs),liposomes,and metal-organic frameworks(MOFs),have been introduced to maximize the therapeutic efficacy of DHA in either single-drug or multidrug therapy.Based on the beneficial properties of NDDSs,including enhanced stability and solubility of the drug,prolonged circulation time and selective accumulation in tumors,the outcomes of DHA-loaded NDDSs for cancer therapy are significantly improved compared to those of free DHA.This reviewfirst summarizes the current understanding of the anticancer mechanisms of DHA and then provides an overview of DHA-including nanomedicines,aiming to provide inspiration for further application of DHA as an anticancer drug.

Targeting cancer stem cells in drug discovery: Current state and future perspectives

In recent decades,cancer stem cells(CSCs)have been increasingly identified in many malignancies.CSC-related signaling pathways and their functions provide new strategies for treating cancer.The aberrant activation of related signaling pathways(e.g.,Wnt,Notch,and Hedgehog pathways)has been linked to multiple types of malignant tumors,which makes these pathways attractive targets for cancer therapy.CSCs display many characteristic features,such as self-renewal,differentiation,high tumorigenicity,and drug resistance.Therefore,there is an urgent need to develop new therapeutic strategies to target these pathways to control stem cell replication,survival,and differentiation.Notable crosstalk occurs among different signaling pathways and potentially leads to compensatory escape.Therefore,multitarget inhibitors will be one of the main methods to overcome the drug resistance of CSCs.Many small molecule inhibitors of components of signaling pathways in CSCs have entered clinical trials,and some inhibitors,such as vismodegib,sonidegib,and glasdegib,have been approved.Tumor cells are susceptible to sonidegib and vismodegib resistance due to mutations in the Smo protein.The signal transducers and activators of transcription 3(STAT3)inhibitor BBI608 is being evaluated in a phase III trial for a variety of cancers.Structural derivatives of BBI608 are the main focus of STAT3 inhibitor development,which is another strategy for CSC therapy.In addition to the potential pharmacological inhibitors targeting CSCrelated signaling pathways,other methods of targeting CSCs are available,such as nano-drug delivery systems,mitochondrion targeting,autophagy,hyperthermia,immunotherapy,and CSC microenvironment targeting.In addition,we summarize the latest advances in the clinical development of agents targeting CSC-related signaling pathways and other methods of targeting CSCs.

Advances in Research of Green Tea Polyphenols in Drug Development

This paper elaborated the chemical components,biological metabolism,and progress in the field of drug development of green tea polyphenols,mainly in the prevention and treatment of cancer,neurodegenerative diseases,and diabetes.The potential anti-tumor activity of tea polyphenols can be achieved through intervening in various stages of tumor generation,development,and metastasis.However,the development of tea polyphenols as a therapeutic drug still faces many challenges,such as low bioavailability.Nanoparticle-based drug delivery systems have particular advantages over the simple tea polyphenols.Since there are emerging safety issues and potential local drug overdose effects,it is necessary to determine the actual dosage and pharmacological mechanism of the drug after encapsulating the nanoparticles.

Relationship and improvement strategies between drug nanocarrier characteristics and hemocompatibility:What can we learn from the literature

This article discusses the various blood interactions that may occur with various types of nano drug-loading systems. Nanoparticles enter the blood circulation as foreign objects. On the one hand, they may cause a series of inflammatory reactions and immune reactions, resulting in the rapid elimination of immune cells and the reticuloendothelial system, affecting their durability in the blood circulation. On the other hand, the premise of the drug-carrying system to play a therapeutic role depends on whether they cause coagulation and platelet activation, the absence of hemolysis and the elimination of immune cells. For different forms of nano drug-carrying systems, we can find the characteristics, elements and coping strategies of adverse blood reactions that we can find in previous researches. These adverse reactions may include destruction of blood cells, abnormal coagulation system, abnormal effects of plasma proteins, abnormal blood cell behavior, adverse immune and inflammatory reactions, and excessive vascular stimulation. In order to provide help for future research and formulation work on the blood compatibility of nano drug carriers.

Microfluidics for nano-drug delivery systems: From fundamentals to industrialization

In recent years,owing to the miniaturization of the fluidic environment,microfluidic technology offers unique opportunities for the implementation of nano drug delivery systems(NDDSs)production processes.Compared with traditional methods,microfluidics improves the controllability and uniformity of NDDSs.The fast mixing and laminar flow properties achieved in the microchannels can tune the physicochemical properties of NDDSs,including particle size,distribution and morphology,resulting in narrow particle size distribution and high drug-loading capacity.The success of lipid nanoparticles encapsulated mRNA vaccines against coronavirus disease 2019 by microfluidics also confirmed its feasibility for scaling up the preparation of NDDSs via parallelization or numbering-up.In this review,we provide a comprehensive summary of microfluidics-based NDDSs,including the fundamentals of microfluidics,microfluidic synthesis of NDDSs,and their industrialization.The challenges of microfluidicsbased NDDSs in the current status and the prospects for future development are also discussed.We believe that this review will provide good guidance for microfluidics-based NDDSs.

The role of caveolin-1 in the biofate and efficacy of anti-tumor drugs and their nano-drug delivery systems

As one of the most important components of caveolae,caveolin-1 is involved in caveolaemediated endocytosis and transcytosis pathways,and also plays a role in regulating the cell membrane cholesterol homeostasis and mediating signal transduction.In recent years,the relationship between the expression level of caveolin-1 in the tumor microenvironment and the prognostic effect of tumor treatment and drug treatment resistance has also been widely explored.In addition,the interplay between caveolin-1 and nano-drugs is bidirectional.Caveolin-1 could determine the intracellular biofate of specifc nano-drugs,preventing from lysosomal degradation,and facilitate them penetrate into deeper site of tumors by transcytosis;while some nanocarriers could also affect caveolin-1 levels in tumor cells,thereby changing certain biophysical function of cells.This article reviews the role of caveolin-1 in tumor prognosis,chemotherapeutic drug resistance,antibody drug sensitivity,and nano-drug delivery,providing a reference for the further application of caveolin-1 in nano-drug delivery systems.

Gather wisdom to overcome barriers:Well-designed nano-drug delivery systems for treating gliomas

Due to the special physiological and pathological characteristics of gliomas,most therapeutic drugs are prevented from entering the brain.To improve the poor prognosis of existing therapies,researchers have been continuously developing non-invasive methods to overcome barriers to gliomas therapy.Although these strategies can be used clinically to overcome the blood-brain barrier(BBB),the accurate delivery of drugs to the glioma lesions cannot be ensured.Nano-drug delivery systems(NDDS)have been widely used for precise drug delivery.In recent years,researchers have gathered their wisdom to overcome barriers,so many well-designed NDDS have performed prominently in preclinical studies.These meticulous designs mainly include cascade passing through BBB and targeting to glioma lesions,drug release in response to the glioma microenvironment,biomimetic delivery systems based on endogenous cells/extracellular vesicles/protein,and carriers created according to the active ingredients of traditional Chinese medicines.We reviewed these well-designed NDDS in detail.Furthermore,we discussed the current ongoing and completed clinical trials of NDDS for gliomas therapy,and analyzed the challenges and trends faced by clinical translation of these well-designed NDDS.

Polymeric nanocarriers for nose-to-brain drug delivery in neurodegenerative diseases and neurodevelopmental disorders

Neurodegenerative diseases are progressive conditions that affect the neurons of the central nervous system(CNS)and result in their damage and death.Neurodevelopmental disorders include intellectual disability,autism spectrum disorder,and attention-deficit/hyperactivity disorder and stem from the disruption of essential neurodevelopmental processes.The treatment of neurodegenerative and neurodevelopmental conditions,together affecting~120 million people worldwide,is challenged by the blood—brain barrier(BBB)and the blood—cerebrospinal fluid barrier that prevent the crossing of drugs from the systemic circulation into the CNS.The nose-to-brain pathway that bypasses the BBB and increases the brain bioavailability of intranasally administered drugs is promising to improve the treatment of CNS conditions.This pathway is more efficient for nanoparticles than for solutions,hence,the research on intranasal nano-drug delivery systems has grown exponentially over the last decade.Polymeric nanoparticles have become key players in the field owing to the high design and synthetic flexibility.This review describes the challenges faced for the treatment of neurodegenerative and neurodevelopmental conditions,the molecular and cellular features of the nasal mucosa and the contribution of intranasal nano-drug delivery to overcome them.Then,a comprehensive overview of polymeric nanocarriers investigated to increase drug bioavailability in the brain is introduced.

The role of tumor-associated macrophages(TAMs) in tumor progression and relevant advance in targeted therapy

Macrophages have a leading position in the tumor microenvironment(TME)which paves the way to carcinogenesis.Initially,monocytes and macrophages are recruited to the sites where the tumor develops.Under the guidance of different microenvironmental signals,macrophages would polarize into two functional phenotypes,named as classically activated macrophages(M1)and alternatively activated macrophages(M2).Contrary to the anti-tumor effect of M1,M2 exerts anti-inflammatory and tumorigenic characters.In progressive tumor,M2 tumor-associated macrophages(TAMs)are in the majority,being vital regulators reacting upon TME.This review elaborates on the role of TAMs in tumor progression.Furthermore,prospective macrophage-focused therapeutic strategies,including drugs not only in clinical trials but also at primary research stages,are summarized followed by a discussion about their clinical application values.Nanoparticulate systems with efficient drug delivery and improved antitumor effect are also summed up in this article.

Smart drug delivery systems for precise cancer therapy

Nano-drug delivery strategies have been highlighted in cancer treatment, and much effort has been made in the optimization of bioavailability, biocompatibility, pharmacokinetics profiles, and in vivo distributions of anticancer nano-drug delivery systems. However, problems still exist in the delicate balance between improved anticancer efficacy and reduced toxicity to normal tissues, and opportunities arise along with the development of smart stimuli-responsive delivery strategies. By on-demand responsiveness towards exogenous or endogenous stimulus, these smart delivery systems hold promise for advanced tumor-specificity as well as controllable release behavior in a spatial-temporal manner. Meanwhile, the blossom of nanotechnology, material sciences, and biomedical sciences has shed light on the diverse modern drug delivery systems with smart characteristics, versatile functions, and modification possibilities. This review summarizes the current progress in various strategies for smart drug delivery systems against malignancies and introduces the representative endogenous and exogenous stimuli-responsive smart delivery systems. It may provide references for researchers in the fields of drug delivery, biomaterials, and nanotechnology.

Pure redox-sensitive paclitaxelemaleimide prodrug nanoparticles: Endogenous albumininduced size switching and improved antitumor efficiency

A commercial albumin-bound paclitaxel nano-formulation has been considered a gold standard against breast cancer.However,its application still restricted unfavorable pharmacokinetics and the immunogenicity of exogenous albumin carrier.Herein,we report an albumin-bound tumor redoxresponsive paclitaxel prodrugs nano-delivery strategy.Using diverse linkages(thioether bond and disulfide bond),paclitaxel(PTX)was conjugated with an albumin-binding maleimide(MAL)functional group.These pure PTX prodrugs could self-assemble to form uniform and spherical nanoparticles(NPs)in aqueous solution without any excipients.By immediately binding to blood circulating albumin after intravenous administration,NPs are rapidly disintegrated into small prodrug/albumin nanoaggregates in vivo,facilitating PTX prodrugs accumulation in the tumor region via albumin receptormediated active targeting.The tumor redox dual-responsive drug release property of prodrugs improves the selectivity of cytotoxicity between normal and cancer cells.Moreover,disulfide bond-containing prodrug/albumin nanoaggregates exhibit long circulation time and superior antitumor efficacy in vivo.This simple and facile strategy integrates the biomimetic characteristic of albumin,tumor redox-responsive on-demand drug release,and provides new opportunities for the development of the high-efficiency antitumor nanomedicines.

Development and application of nano-flavor-drug carriers in neurodegenerative diseases

Neurodegenerative disease is one of the serious diseases of the human nervous system.There is no effective way to treat neurodegenerative diseases.Flavors such as curcumin,coumarin,have attracted increasing attention due to having a beneficial therapeutic effect on Alzheimer＇s disease and Parkinson＇s disease.But the use of most drugs is limited in clinical treatment because of blood-brain barrier.The use of nano-drug carriers such as liposomes,polymer micelles,polymer nanoparticles and magnetic nanoparticles,which can carry drugs across the blood-brain barrier,has brought hope for the treatment of neurodegenerative diseases.