Celastrol-loaded polymeric mixed micelles shows improved antitumor efficacy in 4 T1 bearing xenograft mouse model through spatial targeting.

In this study, we have proposed a novel approach that combines hyaluronic acid (HA), folic acid (FA), and celastrol (CLS) within a polymeric micelle system (CLS-HF/MLs), offering a dual-action strategy against breast cancer. Polymeric mixed micelles were prepared through the thin-film hydration method, and comprehensive quality control parameters were established, encompassing particle size, polydispersity index, zeta potential, surface morphology, encapsulation efficiency, drug content, in vitro drug release, and storage stability assessment. The average particle size of CLS-HF/MLs micelles was found to be 120 nm and their drug loading and encapsulation efficiencies were 15.9 % and 89.52 %, respectively. The in vitro release data showed that the CLS-HF/MLs targeted mixed micelles displayed a prolonged release profile compared to the free drug. Additionally, the stability of the developed polymeric mixed micelles was maintained for up to 8 weeks of storage in terms of particle size and drug content. Furthermore, both flow cytometry and confocal laser scanning microscopy studies indicated a significant enhancement in the cellular uptake efficiency and cytotoxicity of CLS-HF/MLs mixed micelles against MCF-7 cell line. In terms of pharmacokinetic analysis, the half-life and AUC values of CLS-HF/MLs mixed micelles were found to be approximately 4.71- and 7.36-folds higher than the values of free drug (CLS), respectively. The CLS-HF/MLs micelles exhibited remarkable antitumor efficacy (almost complete ablation of the 4 T1-cell bearing tumor xenografts mouse model) due to the dual receptor (CD44 and folate) targeting effects with minimal side effects. When considering the cumulative findings of our present research, it becomes evident that mixed micelles designed for chemotherapy offer a promising and potentially effective therapeutic avenue for the treatment of breast cancer.

Extracellular vesicles-powered immunotherapy: Unleashing the potential for safer and more effective cancer treatment.

Cancer treatment has seen significant advancements with the introduction of Onco-immunotherapies (OIMTs). Although some of these therapies have received approval for use, others are either undergoing testing or are still in the early stages of development. Challenges persist in making immunotherapy widely applicable to cancer treatment. To maximize the benefits of immunotherapy and minimize potential side effects, it's essential to improve response rates across different immunotherapy methods. A promising development in this area is the use of extracellular vesicles (EVs) as novel delivery systems. These small vesicles can effectively deliver immunotherapies, enhancing their effectiveness and reducing harmful side effects. This article discusses the importance of integrating nanomedicines into OIMTs, highlighting the challenges with current anti-OIMT methods. It also explores key considerations for designing nanomedicines tailored for OIMTs, aiming to improve upon existing immunotherapy techniques. Additionally, the article looks into innovative approaches like biomimicry and the use of natural biomaterial-based nanocarriers (NCs). These advancements have the potential to transform the delivery of immunotherapy. Lastly, the article addresses the challenges of moving OIMTs from theory to clinical practice, providing insights into the future of using advanced nanotechnology in cancer treatment.

Exploring nanocarriers as innovative materials for advanced drug delivery strategies in onco-immunotherapies.

In recent years, Onco-immunotherapies (OIMTs) have been shown to be a potential therapy option for cancer. Several immunotherapies have received regulatory approval, while many others are now undergoing clinical testing or are in the early stages of development. Despite this progress, a large number of challenges to the broad use of immunotherapies to treat cancer persists. To make immunotherapy more useful as a treatment while reducing its potentially harmful side effects, we need to know more about how to improve response rates to different types of immunotherapies. Nanocarriers (NCs) have the potential to harness immunotherapies efficiently, enhance the efficiency of these treatments, and reduce the severe adverse reactions that are associated with them. This article discusses the necessity to incorporate nanomedicines in OIMTs and the challenges we confront with current anti-OIMT approaches. In addition, it examines the most important considerations for building nanomedicines for OIMT, which may improve upon current immunotherapy methods. Finally, it highlights the applications and future scenarios of using nanotechnology.

Dacarbazine-primed carbon quantum dots coated with breast cancer cell-derived exosomes for improved breast cancer therapy.

Imprecise targeting of chemotherapeutic drugs often leads to severe toxicity during breast cancer therapy. To address this issue, we have devised a strategy to load dacarbazine (DC) into fucose-based carbon quantum dots (CQDs), which are subsequently coated with exosomes (Ex-DC@CQDs) derived from breast cancer cells. Nanoparticle tracking analysis and western blotting revealed that Ex-DC@CQDs retained the structural and functional characteristics of exosomes. We found that exosomes facilitated the transport of DC@CQDs to cancer cells via heparan sulfate proteoglycan (HSPG) receptors, followed by an augmented depolarization of the mitochondrial membrane potential, ROS generation, and induction of apoptosis leading to cell death. In vivo imaging and pharmacokinetic studies demonstrated enhanced antitumor targeting and efficacy compared to free DC which we attribute to an improved pharmacokinetic profile, a greater tumor accumulation via exosome-mediated- HSPG receptor-driven cell uptake, and sustained release of the Ex-DC@CQDs. Our findings may pave the way for the further development of biologically sourced nanocarriers for breast cancer targeting.

Immobilized doxorubicin and ribociclib carbamate linkers encaged in surface modified cubosomes spatially target tumor reductive environment to enhance antitumor efficacy.

In the present investigation, we have strategically synthesized Glutathione (GSH) stimuli-sensitive analogues using carbamate linkers (CL) of DOX (DOX-CL) and RB (RB-CL) which were then anchored to gold nanoparticles (Au-DOX-CL, Au-RB-CL) using mPEG as a spacer. It was observed that carbamate linkage (CL) with four carbon spacer is critical, to position the terminal thiol group, to access the carbamate group efficiently to achieve GSH-assisted release of DOX and RB in tumor-specific environment. When assessed for GSH reductase activity in MDA-MB 231 cell lines, Au-DOX-CL and Au-RB-CL showed nearly 4.18 and 3.13 fold higher GSH reductive activity as compared to the control group respectively. To achieve spatial tumor targeting with a high payload of DOX and RB, Au-DOX-CL and Au-RB-CL were encapsulated in the cell-penetrating peptide (CPP) modified liquid crystalline cubosomes i.e. CPP-Cu(Au@CL-DR). After internalization, the prototype nanocarriers release respective drugs at a precise GSH concentration inside the tumor tissues, amplifying drug concentration to a tune of five-fold. The drug concentrations remain within the therapeutic window for 72 h with a significant reduction of RB (7.8-fold) and DOX (6-fold) concentrations in vital organs, rendering reduced toxicity and improved survival. Overall, this constitutes a promising chemotherapeutic strategy against cancer and its potential application in the offing.

Hyaluronic acid-engineered Bcl-2 inhibitor nanocrystals for site-specific delivery to breast tumor cells.

Aim: This investigation aims to repurpose venetoclax using hyaluronic acid-coated venetoclax nanocrystals (HA-VEN-NCs) to target breast cancer. Materials & methods: An antisolvent precipitation method was used to fabricate the nanocrystals and optimize them using central composite design. Hyaluronic acid (HA)-coated and -uncoated nanocrystals were compared in terms of in vitro drug release, cell line studies, CD44-expressing breast tumor cell binding capability and anticancer activity. Results: HA-VEN-NCs and venetoclax nanocrystals (VEN-NCs) showed pH-responsive drug-release behavior, exhibiting sustained release at pH 6.8. Our extensive in vitro cell line investigation showed that HA-VEN-NCs efficiently bind to CD44-expressing breast tumor cells and possess excellent anticancer activity (IC50: 2.00 µg/ml) compared with VEN-NCs. Conclusion: Our findings anticipate that HA-VEN-NCs could serve as valuable nanoplatforms for cancer treatments in the future.

Recent updates on innovative approaches to overcome drug resistance for better outcomes in cancer.

The multi-dimensional challenge of drug resistance is one of the pivotal hindrances for cancer chemotherapy. A reductive approach to define and distinguish the main aspects of drug resistance, such as tumor growth kinetics about tumor micro-environment (tumor multifariousness), therapeutic pressure, physical barricades, irreversible genetic mutation, as well as role of the immune system, are the main causes of failure in cancer therapy are presented systematically. We are focusing on general approaches to reduce drug resistance: earlier diagnosis of tumors allowing for cancer halting; dynamic surveillance throughout treatment; the adding of new therapeutic strategies and improve pharmacodynamics precepts resulting in profound effects; and identification of cancerous cells repositories using high-throughput monitoring, as well as the interoperability of clinical- gene mapping statics are described in detail. These strategies could be potentially constructed for any tumor at any precise moment and used to guide therapy selection. Chemotherapeutic agents results in mild improved survival in clinical trials owing to several pathophysiologic obstacles, such as intra-tumoral dispersion, invasion & intra-cellular transportation. This review highlights recent advancements in developing new therapeutic innovations to combat drug resistance in cancer therapy by overcoming various barricades in the tumor microenvironment.

Critical parameters for design and development of multivalent nanoconstructs: recent trends.

A century ago, the groundbreaking concept of the magic bullet was given by Paul Ehrlich. Since then, this concept has been extensively explored in various forms to date. The concept of multivalency is among such advancements of the magic bullet concept. Biologically, the concept of multivalency plays a critical role in significantly huge numbers of biochemical interactions. This concept is the sole reason behind the higher affinity of biological molecules like viruses to more selectively target the host cell surface receptors. Multivalent nanoconstructs are a promising approach for drug delivery by the active targeting principle. Designing and developing effective and target-specific multivalent drug delivery nanoconstructs, on the other hand, remain a challenge. The underlying reason for this is a lack of understanding of the crucial interactions between ligands and cell surface receptors, as well as the design of nanoconstructs. This review highlights the need for a better theoretical understanding of the multivalent effect of what happens to the receptor-ligand complex after it has been established. Furthermore, the critical parameters for designing and developing robust multivalent systems have been emphasized. We have also discussed current advances in the design and development of multivalent nanoconstructs for drug delivery. We believe that a thorough knowledge of theoretical concepts and experimental methodologies may transform a brilliant idea into clinical translation.

COVID-19 Infection: Targeting Possibilities for Treatment.

The outbreak of novel coronavirus (nCoV) or severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) in December 2019 in Wuhan, China, has posed an international public health emergency worldwide and forced people to be confined in their homes. This virus is of high-risk category and is declared a pandemic by the World Health Organization (WHO). The worldwide researchers and various health professionals are working together to determine the best way to stop its spread or halt this virus's spread and circumvent this pandemic condition threatening millions of human lives. The absence of definitive treatment is possible to explore to reduce virus infection and enhance patient recovery. Along with off-label medicines, plasma therapy, vaccines, the researchers exploit the various plants/herbs and their constituents to effectively treat nCoV infection. The present study aimed to present brief and most informative salient features of the numerous facts regarding the SARS-CoV-2, including the structure, genomic sequence, recent mutation, targeting possibility, and various hurdles in research progress, and off-labeled drugs, convalescent plasma therapy, vaccine and plants/herbs for the treatment of coronavirus disease-2019 (COVID-19). Results showed that off-labeled drugs such as hydroxychloroquine, dexamethasone, tocilizumab, antiviral drug (remdesivir, favipiravir), etc., give positive results and approved for use or approved for restricted use in some countries like India. Future research should focus on these possibilities that may allow the development of an effective treatment for COVID-19.

Carbopol-olive oil-based bigel drug delivery system of doxycycline hyclate for the treatment of acne.

OBJECTIVE: The objective of this study was to prepare and evaluate the doxycycline hyclate containing bigel for the effective treatment of acne. METHODS: Bigels are biphasic systems formed by water-based hydrogels and oil-based organogel. Carbopol 940 was used to prepare the hydrogel phase, whereas Span-60 and olive oil for the oleogel phase. RESULTS: The microstructure of bigel confirmed the oil in water type emulsion formation. The average droplet size of formulations was found 15-50 µm, and a bell-shaped droplet distribution curve, rheological, or viscosity studies suggested that the consistency and stability of bigel decrease with high organogel concentration. Three formulations (F1, F2, and F3) of the different ratios of hydrogel:oleogel (60:40, 70:30, and 80:20) were prepared in which F1 was less stable compared to F2 and F3. The drug content of F2 and F3 was respectively 79.94 and 71.33%. Formulation F2 was found more effective as compared to F3 based on in vitro drug release studies. Bigel also showed better results during in vivo studies at the rabbit ear model, which reduce acne diameter up to 1.10 mm from 4.9 mm while gel reduced it up to 1.20 mm.

Multiple roles of active stiffness in upright balance and multidirectional sway.

Both passive and active mechanisms are necessary to explain small amplitude forward-backward (FB) voluntary swaying. Parallel and symmetric leg inverted pendulum models with stiffness control are a simple way to replicate FB swaying during quiet stance. However, it has been more difficult to model lateral left-right (LR) voluntary swaying involving the dual mechanisms of hip loading-unloading and ankle pressure distribution. To assess these factors, we had subjects perform small amplitude FB and LR sways and circular rotation. We experimentally identified three parameters that characterized their two-dimensional stiffnesses: AP stiffness (KSAP), and lateral stiffness (KSML), at the ankles and a parameter we refer to as the engagement-disengagement rate (KED) of the legs. We performed simulations with our engaged leg model (Bakshi A, DiZio P, Lackner JR. J Neurophysiol 121: 2042-2060, 2019; Bakshi A, DiZio P, Lackner JR. J Neurophysiol 121: 2028-2041, 2019) to test its predictions about the limits of balance stability during sway in the three test conditions. Comparing the model's predictions with the experimental data, we found that KSAP has a task-dependent dual role in upright balance and is crucial to prevent falling; KSML helps overcome viscous drags but is not instrumental to stability; KED has a key role in stability and is dependent on the biomechanical geometry of the body, which is invariant across balance tasks. These findings provide new insights into balance control that have important clinical implications for falling, especially for patients who are unable to use a hip strategy during balance control.NEW & NOTEWORTHY Our previously published Engaged Leg Model here shows how stiffness plays complex multicausal roles in balance. In one role, it is crucial to stability, with task contingent influences over balance. In another, it overcomes viscous drag. Task-dependent stiffness alone does not explain stable balance; geometrical, invariant aspects of body biomechanics also matter. Our model is fully applicable to clinical balance pathologies involving asymmetries in movement and balance control.

The effect of hypergravity on upright balance and voluntary sway.

We compared voluntary oscillatory sway for eight subjects tested in 1.8-g and 1-g gravito-inertial force (GIF) levels of parabolic flight. Subjects performed voluntary forward-backward (FB) and lateral left-right (LR) swaying as the forces and moments under the soles of each foot were measured. We calculated the experimental values of three parameters: two ankle stiffness parameters KSAP and KSML acting in orthogonal FB and LR directions and one parameter KED related to leg pivot shifting. Simulations of the engaged leg model (Bakshi A, DiZio P, Lackner JR. J Neurophysiol 121: 2042-2060, 2019; Bakshi A, DiZio P, Lackner JR. J Neurophysiol 121: 2028-2041, 2019) correctly predicted the experimentally determined stability bounds of upright balance and also the scaling of the postural parameters as a function of GIF magnitude. The effective stiffness, KSAP, at the ankles played the primary role to prevent falling in FB swaying and both model predictions, and experimental data showed KSAP to scale up in proportion to GIF magnitude. For LR swaying, the model predicted a 3:4 scaling of anterior-posterior stiffness to change in GIF magnitude, which was borne out by the experimental data. Simulations predict stability (nonfalling) not to depend on lateral stiffness, KSML, which was experimentally found not to depend on the GIF magnitude. Both model and experiment showed that the geometry-dependent pivot shift parameter KED was invariant to a change in GIF magnitude. Thus the ELM explains voluntary sway and balance in altered GIF magnitude conditions, rotating environments with Coriolis perturbations of sway, as well as normal terrestrial conditions.NEW & NOTEWORTHY A nonparallel leg model of balance, the engaged leg model (ELM), was previously developed to characterize adaptive balance control in a rotating environment. Here we show the ELM also explains sway in hypergravity. It predicts the changes in balance control parameters with changes in gravity. ELM is currently the only balance model applicable to artificial and hypergravity conditions. ELM can also be applied to terrestrial clinical situations for pathologies that generate postural asymmetries.

Rapid adaptation to Coriolis force perturbations of voluntary body sway.

Studying adaptation to Coriolis perturbations of arm movements has advanced our understanding of motor control and learning. We have now applied this paradigm to two-dimensional postural sway. We measured how subjects (n = 8) standing at the center of a fully enclosed rotating room who made voluntary anterior-posterior swaying movements adapted to the Coriolis perturbations generated by their sway. Subjects underwent four voluntary sway trials prerotation, 20 per-rotation at 10 rpm counterclockwise, and 10 postrotation. Each trial lasted 20 s, and subjects were permitted normal vision. Their voluntary sway during rotation generated Coriolis forces that initially induced rightward deviations of their forward sway paths and leftward deviations of their backward sway. Sagittal plane sway was gradually restored over per-rotation trials, and a mirror image aftereffect occurred in postrotation trials. Dual force plate data analysis showed that subjects learned to counter the Coriolis accelerations during rotation by executing a bimodal torque pattern that was asymmetric across legs and contingent on forward vs. backward movement. The experience-dependent acquisition and washout of this compensation indicate that an internal, feedforward model underlies the leg-asymmetric bimodal torque compensation, contingent on forward vs. backward movement. The learned torque asymmetry we observed for forward vs. backward sway is not consistent with parallel two-leg models of postural control. NEW & NOTEWORTHY This paper describes adaptation to Coriolis force perturbations of voluntary sway in a rotating environment. During counterclockwise rotation, sway paths are deviated clockwise, but full restoration of fore-aft sway is regained in minutes. Negative aftereffects are briefly present postrotation. Current parallel leg models of postural control cannot account for these findings, which show that postural control, like arm movement control, can adapt rapidly and completely to the Coriolis forces generated in artificial gravity environments.

Adaptation to Coriolis force perturbations of postural sway requires an asymmetric two-leg model.

In the companion paper (Bakshi A, DiZio P, Lackner JR. J Neurophysiol. In press, 2019), we reported how voluntary forward-backward sway in a rotating room generated medial-lateral Coriolis forces that initially deviated intended body sway paths. Pure fore-aft sway was gradually restored over per-rotation trials, and a negative aftereffect occurred during postrotation sway. Force plate recordings showed that subjects learned to compensate for the Coriolis forces by executing a bimodal torque, the distribution of which was asymmetric across the two legs and of opposite sign for forward vs. backward sway. To explain these results, we have developed an asymmetric, nonparallel-leg, inverted pendulum model to characterize upright balance control in two dimensions. Fore-aft and medial-lateral sway amplitudes can be biomechanically coupled or independent. Biomechanical coupling occurs when Coriolis forces orthogonal to the direction of movement perturb sway about the ankles. The model includes a mechanism for alternating engagement/disengagement of each leg and for asymmetric drive to the ankles to achieve adaptation to Coriolis force-induced two-dimensional sway. The model predicts the adaptive control underlying the adaptation of voluntary postural sway to Coriolis forces. A stability analysis of the model generates parameter values that match those measured experimentally, and the parameterized model simulations reproduce the experimentally observed sway trajectories. NEW & NOTEWORTHY This paper presents a novel nonparallel leg model of postural control that correctly predicts the perturbations of voluntary sway that occur in a rotating environment and the adaptive changes that occur to restore faithful movement trajectories. This engaged leg model (ELM) predicts the asymmetries in force distribution and their patterns between the two legs to restore accurate movement trajectories. ELM has clinical relevance for pathologies that generate postural asymmetries and for altered gravitoinertial force conditions.

The influence of sleep deprivation and oscillating motion on sleepiness, motion sickness, and cognitive and motor performance.

Our goal was to determine how sleep deprivation, nauseogenic motion, and a combination of motion and sleep deprivation affect cognitive vigilance, visual-spatial perception, motor learning and retention, and balance. We exposed four groups of subjects to different combinations of normal 8h sleep or 4h sleep for two nights combined with testing under stationary conditions or during 0.28Hz horizontal linear oscillation. On the two days following controlled sleep, all subjects underwent four test sessions per day that included evaluations of fatigue, motion sickness, vigilance, perceptual discrimination, perceptual learning, motor performance and learning, and balance. Sleep loss and exposure to linear oscillation had additive or multiplicative relationships to sleepiness, motion sickness severity, decreases in vigilance and in perceptual discrimination and learning. Sleep loss also decelerated the rate of adaptation to motion sickness over repeated sessions. Sleep loss degraded the capacity to compensate for novel robotically induced perturbations of reaching movements but did not adversely affect adaptive recovery of accurate reaching. Overall, tasks requiring substantial attention to cognitive and motor demands were degraded more than tasks that were more automatic. Our findings indicate that predicting performance needs to take into account in addition to sleep loss, the attentional demands and novelty of tasks, the motion environment in which individuals will be performing and their prior susceptibility to motion sickness during exposure to provocative motion stimulation.

Statistical analysis of quiet stance sway in 2-D.

Subjects exposed to a rotating environment that perturbs their postural sway show adaptive changes in their voluntary spatially directed postural motion to restore accurate movement paths but do not exhibit any obvious learning during passive stance. We have found, however, that a variable known to characterize the degree of stochasticity in quiet stance can also reveal subtle learning phenomena in passive stance. We extended Chow and Collins (Phys Rev E 52(1):909-912, 1995) one-dimensional pinned-polymer model (PPM) to two dimensions (2-D) and then evaluated the model's ability to make analytical predictions for 2-D quiet stance. To test the model, we tracked center of mass and centers of foot pressures, and compared and contrasted stance sway for the anterior-posterior versus medio-lateral directions before, during, and after exposure to rotation at 10 rpm. Sway of the body during rotation generated Coriolis forces that acted perpendicular to the direction of sway. We found significant adaptive changes for three characteristic features of the mean square displacement (MSD) function: the exponent of the power law defined at short time scales, the proportionality constant of the power law, and the saturation plateau value defined at longer time scales. The exponent of the power law of MSD at a short time scale lies within the bounds predicted by the 2-D PPM. The change in MSD during exposure to rotation also had a power-law exponent in the range predicted by the theoretical model. We discuss the Coriolis force paradigm for studying postural and movement control and the applicability of the PPM model in 2-D for studying postural adaptation.

Adaptation to Coriolis perturbations of voluntary body sway transfers to preprogrammed fall-recovery behavior.

In a rotating environment, goal-oriented voluntary movements are initially disrupted in trajectory and endpoint, due to movement-contingent Coriolis forces, but accuracy is regained with additional movements. We studied whether adaptation acquired in a voluntary, goal-oriented postural swaying task performed during constant-velocity counterclockwise rotation (10 RPM) carries over to recovery from falling induced using a hold and release (H&R) paradigm. In H&R, standing subjects actively resist a force applied to their chest, which when suddenly released results in a forward fall and activation of an automatic postural correction. We tested H&R postural recovery in subjects (n = 11) before and after they made voluntary fore-aft swaying movements during 20 trials of 25 s each, in a counterclockwise rotating room. Their voluntary sway about their ankles generated Coriolis forces that initially induced clockwise deviations of the intended body sway paths, but fore-aft sway was gradually restored over successive per-rotation trials, and a counterclockwise aftereffect occurred during postrotation attempts to sway fore-aft. In H&R trials, we examined the initial 10- to 150-ms periods of movement after release from the hold force, when voluntary corrections of movement path are not possible. Prerotation subjects fell directly forward, whereas postrotation their forward motion was deviated significantly counterclockwise. The postrotation deviations were in a direction consistent with an aftereffect reflecting persistence of a compensation acquired per-rotation for voluntary swaying movements. These findings show that control and adaptation mechanisms adjusting voluntary postural sway to the demands of a new force environment also influence the automatic recovery of posture.