Emerging avenues for the management of cerebral malaria.

OBJECTIVES: Cerebral malaria (CM) is a lethal complication of Plasmodium falciparum infection. The multifactorial pathogenesis of the disease involving parasitic invasion of erythrocytes and sequestration of infected erythrocytes within the cerebral blood vessels leading to neuroinflammation and blood-brain barrier (BBB) disruption demands a multi-pronged treatment strategy. This article gives a brief overview of the pathogenesis of CM, challenges associated with its treatment and potential strategies to combat the same. KEY FINDINGS: There are several roadblocks in the successful treatment of CM. Resistance to artemisinin-based therapies has been reported in malaria-endemic regions. The paucity of targeted delivery to the brain necessitates the administration of antimalarials such as quinine in large doses causing toxic effects. There is a need for compounds to prevent oxidative stress, neuroinflammation and BBB disruption to decrease the menace of neurological sequelae associated with CM. SUMMARY: Extensive research endeavours are now oriented towards investigating compounds that can act against neuroinflammation; developing brain-targeted nanocarriers to selectively deliver therapeutics against CM; and repurposing existing drugs and a combination of antimalarial and anti-inflammatory or immunomodulatory molecules for the treatment of CM. Protocols for evaluating novel proposed therapies against CM should be revisited to integrate monitoring of neurological parameters in parallel with the estimation of parasite load and survival.

Nanocarriers as versatile delivery systems for effective management of acne.

Acne vulgaris is a chronic inflammatory skin disorder affecting mostly females. It has a negative impact on the social life and psychological well-being of the individual. Its pathogenesis involves an exaggerated secretion of sebum, hyperkeratinisation of hair follicles, colonization of anaerobic microbes in the hair follicles, and inflammation. Conventional therapy for acne utilizes antibacterial and anti-inflammatory drugs. Systemic use of these drugs is associated with undesirable toxicities. Hence, topical delivery of anti-acne drugs is desired. However, topical delivery is hindered by poor aqueous solubility of drug and inadequate penetration across stratum corneum. Nanocarriers are endowed with immense potential to facilitate topical delivery of anti-acne drugs as monotherapy or in combination by a myriad of mechanisms including occlusive nature promoting skin hydration, providing sustained drug release thereby decreasing dosing frequency, follicular targeting, and protecting the labile active from degradation. Further, smart nanocarriers can deliver the anti-acne cargo in response to some stimulus present at the disease site precluding undesirable effects at non target sites. Nanocarriers have also been explored in photothermal and photodynamic therapy of acne for destruction of antibiotic resistant bacteria implicated in acne. This review focuses on the potential of a variety of nanocarriers for treatment of acne.

Cancer cell fusion: a potential target to tackle drug-resistant and metastatic cancer cells.

Cell fusion is an integral, established phenomenon underlying various physiological processes in the cell cycle. Although research in cancer metastasis has hypothesised numerous molecular mechanisms and signalling pathways responsible for invasion and metastasis, the origin and progression of metastatic cells within primary tumours remains unclear. Recently, the role of cancer cell fusion in cancer metastasis and development of multidrug resistance (MDR) in tumours has gained prominence. However, evidence remains lacking to justify the role of cell fusion in cancer metastasis and drug resistance. Here, we highlight plausible mechanisms governing cell fusion with different cell types in the tumour microenvironment (TME), the clinical relevance of cancer cell fusion, its potential as a target for overcoming MDR and inhibiting metastasis, and putative modes of treatment.

Emerging vistas in theranostic medicine.

Recent years have witnessed a paradigm shift in the focus of healthcare towards development of customized therapies which cater to the unmet needs in a myriad of disease areas such as cancer, infections, cardiovascular diseases, neurodegenerative disorders and inflammatory disorders. The term 'theranostic' refers to such multifunctional systems which combine the features of diagnosis and treatment in a single platform for superior control of the disease. Theranostic systems enable detection of disease, treatment and real time monitoring of the diseased tissue. Theranostic nanocarriers endowed with multiple features of imaging, targeting, and providing on-demand delivery of therapeutic agents have been designed for enhancement of therapeutic outcomes. Fabrication of theranostics involves utilization of materials having distinct properties for imaging, targeting, and programming drug release spatially and temporally. Although the field of theranostics has been widely researched and explored so far for treatment of different types of cancer, there have been considerable efforts in the past few years to extend its scope to other areas such as infections, neurodegenerative disorders and cardiovascular diseases. This review showcases the potential applications of theranostics in disease areas other than cancer. It also highlights the cardinal issues which need to be addressed for successful clinical translation of these theranostic tools.

Nanosoldiers: A promising strategy to combat triple negative breast cancer.

The phenomenal rise in cancer over the past few years has made it the second leading cause of death worldwide. Breast cancer constitutes the predominant cancer encountered in women. Triple negative breast cancer (TNBC) is the most notorious form of breast cancer which involves absence of the estrogen, progesterone and human epidermal growth factor receptor (EGFR) on breast cancer cells. It is a real challenge for oncologists owing to the recurrence and metastasis which result in poor prognosis. Conventional therapies employed in treatment of TNBC suffer from issues of poor bioavailability, poor cellular uptake, resistance, and undesirable off-site toxicities. Nanosized delivery systems, herein designated as nanosoldiers can be smartly designed to be equipped with multiple weapons (drugs, genetic materials, photosensitizers, etc.) to fight the battle against recalcitrant TNBC in a myriad of ways such as bioavailability enhancement, targeted uptake by the TNBC cells, on-demand drug delivery at tumour site, combination therapy, multimodal therapy, photodynamic therapy, photothermal therapy, anti-metastatic approaches, theranostics, etc. The versatility of nanosoldiers with respect to their material of composition, their mechanism of drug loading and release, ability to modify in vivo drug disposition, multifunctional characteristics enabling detection, treatment, and monitoring, etc. endows them with incredible potential to destroy the intractable TNBC cells. The focus of the review is to highlight the extraordinary potential of nanocarriers in treatment of TNBC and few challenges which need to be overcome for these nanosoldiers to form a part of the clinical armamentarium of anticancer agents.

Nanostructured lipid carriers of artemether-lumefantrine combination for intravenous therapy of cerebral malaria.

Patients with cerebral malaria (CM) are unable to take oral medication due to impaired consciousness and vomiting thus necessitating parenteral therapy. Quinine, artemether, and artesunate which are currently used for parenteral malaria therapy have their own drawbacks. The World Health Organization (WHO) has now banned monotherapy and recommends artemisinin-based combination therapy for malaria treatment. However, presently there is no intravenous formulation available for combination therapy of malaria. Artemether-Lumefantrine (ARM-LFN) is a WHO approved combination for oral malaria therapy. However, the low aqueous solubility of ARM and LFN hinders their intravenous delivery. The objective of this study was to formulate ARM-LFN nanostructured lipid carriers (NLC) for intravenous therapy of CM. ARM-LFN NLC were prepared by microemulsion template technique and characterized for size, drug content, entrapment efficiency, drug release, crystallinity, morphology, amenability to autoclaving, compatibility with infusion fluids, stability, antimalarial efficacy in mice, and toxicity in rats. The ARM-LFN NLC showed sustained drug release, amenability to autoclaving, compatibility with infusion fluids, good stability, complete parasite clearance and reversal of CM symptoms with 100% survival in Plasmodium berghei-infected mice, and safety in rats. The biocompatible ARM-LFN NLC fabricated by an industrially feasible technique offer a promising solution for intravenous therapy of CM.

Artemether-lumefantrine nanostructured lipid carriers for oral malaria therapy: Enhanced efficacy at reduced dose and dosing frequency.

Artemether-lumefantrine (ARM-LFN) is a World Health Organization (WHO) approved fixed-dose combination having low solubility and poor oral bioavailability. Nanostructured lipid carriers (NLC) were developed to enhance the oral efficacy of this combination using the microemulsion template technique. They were characterized for drug content, entrapment efficiency, size distribution, in vitro release, antimalarial efficacy, and toxicity. The NLC showed sustained drug release. The recommended adult therapeutic dose is 80mg ARM and 480mg LFN (4 tablets) twice a day, which amounts to 160mg ARM and 960mg LFN daily. ARM-LFN NLC given once a day at 1/5 of therapeutic dose (16mg ARM and 96mg LFN) showed complete parasite clearance and 100% survival in Plasmodium berghei-infected mice. 33% of the mice treated with marketed tablets twice a day at the therapeutic dose showed late-stage recrudescence. Thus, NLC showed enhanced efficacy at 1/10 of the daily dose of ARM-LFN. The 10-fold reduced daily dose was formulated in two soft gelatin capsules thus reducing the number of units to be taken at a time by the patient. The capsules showed good stability at room temperature for a year. The NLC were found to be safe in rats. The biocompatible NLC developed using an industrially feasible technique offer a promising solution for oral malaria therapy.

Bioavailability enhancement of atovaquone using hot melt extrusion technology.

Emerging parasite resistance and poor oral bioavailability of anti-malarials are the two cardinal issues which hinder the clinical success of malaria chemotherapy. Atovaquone-Proguanil is a WHO approved fixed dose combination used to tackle the problem of emerging resistance. However, Atovaquone is a highly lipophilic drug having poor aqueous solubility (less than 0.2 µg/ml) thus reducing its oral bioavailability. The aim of the present investigation was to explore hot melt extrusion (HME) as a solvent-free technique to enhance solubility and oral bioavailability of Atovaquone and to develop an oral dosage form for Atovaquone-Proguanil combination. Solid dispersion of Atovaquone was successfully developed using HME. The solid dispersion was characterized for DSC, FTIR, XRD, SEM, and flow properties. It was filled in size 2 hard gelatin capsules. The formulation showed better release as compared to Malarone® tablets, and 3.2-fold and 4.6-fold higher bioavailability as compared to Malarone® tablets and Atovaquone respectively. The enhanced bioavailability also resulted in 100% anti-malarial activity in murine infection model at 1/8(th) therapeutic dose. Thus the developed methodology shows promising potential to solve the problems associated with Atovaquone therapy, namely its high cost and poor oral bioavailability, resulting in increased therapeutic efficacy of Atovaquone.

Dissolution enhancement of atorvastatin calcium by co-grinding technique.

Atorvastatin calcium (AC) is a BCS class II drug which shows poor bioavailability due to inadequate dissolution. Solid dispersions present a promising option to enhance the solubility of poorly soluble drugs. Co-grinding with hydrophilic excipients is an easy and economical technique to improve the solubility of poorly soluble drugs and is free from usage of organic solvents. The aim of the present study was to explore novel carrier VBP-1 (organosulphur compound) for formulating a solid dispersion by using a simple, commercially viable co-grinding technique to enhance the dissolution of AC and to develop an oral formulation of the same. Composition of the solid dispersion was optimized based on the release profile in pH 1.2 buffer. The optimized solid dispersion was further characterized for flow properties, DSC, FTIR spectroscopy, XRD, contact angle, SEM studies and release profile in phosphate buffer pH 6.8. The developed solid dispersion gave similar release profile as the innovator formulation (Lipitor® tablets) in both pH 1.2 buffer and phosphate buffer pH 6.8. The developed solid dispersion was formulated into hard gelatin capsules (size 3). The developed capsules were found to give similar release as the innovator formulation in both pH 1.2 buffer and phosphate buffer pH 6.8. The developed capsules were found to be stable for a period of 6 months. Anti-hyperlipidemic efficacy studies in rats showed higher reduction in cholesterol and triglyceride levels by the developed capsules in comparison to pure AC. In conclusion, novel carrier VBP-1 was successfully employed to enhance the dissolution of AC using co-grinding technique.

Parasite impairment by targeting Plasmodium-infected RBCs using glyceryl-dilaurate nanostructured lipid carriers.

Antimalarial therapy is a major contributor to declining malaria morbidity and mortality. However, the high toxicity and low bioavailability of current antimalarials and emerging drug resistance necessitates drug-delivery research. We have previously developed glyceryl-dilaurate nanolipid carriers (GDL-NLCs) for antimalarial drug delivery. Here, we show evidence that GDL-NLCs themselves selectively target Plasmodium-infected red blood cells (iRBCs), and cause severe parasite impairment. The glyceryl-dilaurate lipid-moiety was important in the targeting. GDL-NLCs localized to the parasite mitochondrion and uptake led to mitochondrial-membrane polarization and Ca(2+) ion accumulation, ROS release, and stage-specific iRBC lysis. GDL-NLC treatment also resulted in externalization of iRBC-membrane phosphatidylserine and enhanced iRBC clearance by macrophages. GDL-NLC uptake disrupted the parasite-induced tubulovesicular network, which is vital for nutrient import by the parasite. Laser optical trap studies revealed that GDL-NLCs also restored iRBC flexibility. Such restoration of iRBC flexibility may help mitigate the vasculature clogging that can lead to cerebral malaria. We demonstrate the suitability of GDL-NLCs for intravenous delivery of antimalarial combinations artemether-clindamycin and artemether-lumefantrine in the murine model. Complete parasite clearance was achieved at 5-20% of the therapeutic dose of these combinations. Thus, this nanostructured lipid formulation can solubilize lipophilic drugs, selectively target and impair the parasite-infected red cell, and therefore constitutes a potent delivery vehicle for antimalarials.

The upcoming field of theranostic nanomedicine: an overview.

Nanocarriers have drastically changed the face of health care by making a mark in diverse arenas of diagnosis, drug delivery, and gene delivery to name a few. The recent feat in nanotechnology has been the birth of nanotheranostics which aims at blending both therapeutic and diagnostic functions within a single nanoscaffold. The field of theranostic nanomedicine is a result of fruitful advances in fields of material science, imaging modalities, formulation development, and molecular biology. Theranostic nanomedicine that was at first developed for enhancing the quality of treatment meted out to cancer patients has now been explored even in atherosclerosis and infections, albeit to a lower extent. The review summarizes various types of nanocarriers that have been explored with one or sometimes multiple imaging modalities for an array of applications ranging from drug delivery and gene delivery to photosensitizing agent delivery for photodynamic therapy. The article also highlights the few but significant developments made in the field of theranostic nanomedicine for atherosclerosis and infections. In conclusion, theranostic nanomedicine is a rapidly growing field. However, there are a few problems that need to be addressed before theranostic nanocarriers carve a niche for themselves in the clinic.

Novel targets for malaria therapy.

Malaria has emerged as one of the most debilitating parasitic infection with about 500 million cases reported annually and one million deaths worldwide. Currently, Plasmodium falciparum has developed resistance to almost all classes of antimalarials, thus precluding the use of those agents which once formed the cornerstone of malaria therapy. In lieu of this phenomenon, and taking into consideration the absence of an effective vaccine for malaria, the only way to combat the deadly parasite is to enrich the antimalarial cache with new molecules acting on fresh targets in the parasite. After potential targets have been validated, these targets can be used as basis for screening compounds to identify new leads followed by lead optimization. This review discusses novel targets of the malaria parasite that can be utilized to treat the disease.