Dendrimer-mediated targeting of angiogenic biomarkers: therapeutic intervention against cancer.

INTRODUCTION: Development of novel vascular networks is a fundamental requirement for tumor growth and progression. In the last decade, biomarkers and underlying molecular pathways of angiogenesis have been intensely investigated to disrupt the initiation and progression of tumor angiogenesis. However, the clinical applications of anti-angiogenic agents are constrained due to toxic side effects, acquired drug resistance and unavailability of validated biomarkers. AREA COVERED: This review discusses the development of dendrimeric nanocarriers that could be a promising domain to explore for the eradication of current challenges associated with angiogenesis-based cancer therapy. Novel drug-delivery approaches with subtle readouts and better understanding of molecular mechanisms have revealed that dendrimers comprise innate anti-angiogenic activity and incorporation of anti-angiogenic agents or gene-silencing RNA could lead to synergistic anti-angiogenic and anticancer effects with reduced side effects. EXPERT OPINION: Dendrimer-mediated targeting of angiogenic biomarkers have efficiently led to the vascular normalization, and rational linking of dendrimers with anti-angiogenic agent or siRNA or both might be a potential area to eradicate the current challenges of angiogenesis-based cancer therapy. However, drawbacks associated with the dendrimers-mediated targeting of angiogenic biomarkers, such as poor stability or small expression of these biomarkers on the normal cells, limits it application at market scale.

Quality by design (QbD) approach-based development of optimized nanocarrier to achieve quality target product profile (QTPP)-targeted lymphatic delivery.

Background.Insulin, commonly used for diabetes treatment, needs better ways to improve its effectiveness and safety due to its challenges with poor permeability and stability. Various system has been developed for oral peptide delivery. The non-targeted system can prevent gastric and enzymatic degradation of peptides but cannot increase the bulk transport of peptides across the membrane. However, the non-selectivity is the limitation of the existing system. Numerous carbohydrate-binding receptors overexpressed on intestinal macrophage cells (M-cells) of gut-associated lymphoid tissue. It is the most desirable site for receptor-mediated endocytosis and lymphatic drug delivery of peptides.Objective. The prime objective of the study was to fabricate mannose ligand conjugated nanoparticles (MNPs) employing a quality-by-design approach to address permeability challenges after oral administration. Herein, the study's secondary objective of this study is to identify the influencing factor for producing quality products. Considering this objective, the Lymphatic uptake of NPs was selected as a quality target product profile (QTPP), and a systematic study was conducted to identify the critical formulation attributes (CFAs) and critical process parameters (CPP) influencing critical quality attributes (CQAs). Mannosylated Chitosan concentrations (MCs) and TPP concentrations were identified as CFAs, and stirring speed was identified as CPP.Methods. MNPs were prepared by the inotropic gelation method and filled into the enteric-coated capsule to protect from acidic environments. The effect of CFAs and CPP on responses like particle size (X) and entrapment (Y) was observed by Box-Behnken design (BBD). ANOVA statistically evaluated the result to confirm a significant level (p< 0.05). The optimal conditions of NPs were obtained by constructing an overlay plot and determining the desirability value. HPLC and zeta-seizer analysis characterized the lyophilized NPs. Cell-line studies were performed to confirm the safety and M-cell targeting of NPs to enhance Insulin oral bioavailability.Results. The morphology of NPs was revealed by SEM. The developed NPs showed a nearly oval shape with the average size, surface potential, and % drug entrapment were 245.52 ± 3.37 nm, 22.12 ± 2.13 mV, and 76.15 ± 1.3%, respectively. MTT assay result exhibited that MNPs safe and Confocal imaging inference that NPs selectively uptake by the M-cell.Conclusion. BBD experimental design enables the effective formulation of optimized NPs. The statistical analysis estimated a clear assessment of the significance of the process and formulation variable. Cell line study confirms that NPs are safe and effectively uptake by the cell.

Isolated unilateral thalamic venous infarct in a toddler.

Isolated deep cerebral venous thrombosis (CVT), especially involving only the right thalamus, is one of the rarest forms of intracranial venous thrombosis in a child. The anatomy and flow patterns of the deep cerebral venous system are complex and usually, the thrombosis of the internal cerebral veins (ICV) results in thalamic infarction bilaterally. The focal infections, thalamic tumours and vascular malformations may have overlapping clinicoradiological patterns. The treating team should be able to recognise the atypical phenotypes of the deep CVT at the earliest, which can facilitate apt treatment and obviate the need for unnecessary investigations and interventions. We present a rare case of an isolated right thalamic acute venous infarct secondary to bilateral ICV thrombosis in a toddler who was successfully managed by timely diagnosis and with only conservative therapy.

Pharmaceutical Applications of Quantum Dots.

Nanotechnology has been utilized in developing novel drug formulations with minimal adverse effects. Nanoparticles in a lower size range with great surface area, increased potency, and easy permeability could be an approach for the treatment of cancer and other diseases. Unlike other nanoparticles, quantum dots have specific functional groups, have charges over their surface, and are extremely small in size (2-10nm), which makes them more permeable through tight junctions. Quantum dots are interesting materials that offer diagnosis and treatment concurrently. Quantum dots are reported to have several applications in pharmaceuticals as well as drug delivery, diagnosis, immunolabeling, and cell labeling tools. However, the existence of heavy metals in quantum dots such as cadmium poses a potential challenge for future medical applications, where quantum dots may be deliberately injected into the body. In this review, we are focusing on various pharmaceutical applications of quantum dots. Graphical Abstract.

Biomedical Applications and Toxicological Aspects of Functionalized Carbon Nanotubes.

Currently, nanomedicines exhibit implausible capability in overcoming the hurdles faced in gene therapy, cancer treatments, as well as other life-threatening diseases. Worldwide, the unique features of carbon nanotubes (CNTs) are still being explored by researchers to tap their potential. Different types of CNTs exhibit capabilities in the transportation of vaccines, bioactives, and nucleic acids deep into the cell to previously unreachable targets. This review sheds light on the different aspects of biomedical applications and toxicities associated with functionalized CNTs. To better understand the biomedical scope of CNTs, more research into the toxicological behavior of CNTs as well as functionalized CNTs is needed. The exploration of appropriate cell lines to investigate specific receptors and intracellular targets as well as long-term toxicity beyond the proof-of-concept is needed. These issues facing the translation of surface-engineered CNT nanoarchitectures are vital to moving CNT applications from the laboratory to the clinic. The future of pharmaceutical as well as biomedical applications of CNTs will certainly depend upon whether we are able to prove their safety beyond doubt. And if we succeed through vigorous research efforts, then CNTs will have tremendous application as a freely available and economic biomaterial.

Advances in siRNA delivery in cancer therapy.

RNA interference (RNAi)-based therapeutic approaches are under vibrant scrutinisation to seek cancer cure. siRNA suppress expression of the carcinogenic genes by targeting the mRNA expression. However, in vivo systemic siRNA therapy is hampered by the barriers such as poor cellular uptake, instability under physiological conditions, off-target effects and possible immunogenicity. To overcome these challenges, systemic siRNA therapy warrants the development of clinically suitable, safe, and effective drug delivery systems. Herein, we review the barriers, potential siRNA drug delivery systems, and application of siRNA in clinical trials for cancer therapy. Further research is required to harness the full potential of siRNA as a cancer therapeutic.

Pharmaceutical potential of quantum dots.

Quantum dots (QDs) or fluorescent nanocrystals are designed nanoparticles that are promising for several biological and bio-medical applications as well as drug delivery and simultaneous cellular imaging. QD's have exhibited promising potential primarily in receptor based targeting as a result of their distinctive physicochemical properties. Functionalized QDs (f-QDs) have been developed as effective, safe, nano-sized smart systems to deliver a wide range of bio-actives. Surface modified fluorescent carbon QDs with surface modification have attracted attention as targeting ligand to accomplish cellular targeting with enhanced specificity. Several surface engineered and conjugated fluorescent carbon QDs are presently being explored for the treatment of cancer and the outcome is eagerly awaited.

Development and evaluation of targeting ligand-anchored CNTs as prospective targeted drug delivery system.

Our main investigation in the present research was to developt and evaluate targeting ligand-anchored multiwalled carbon nanotubes (MWCNTs) as prospective targeted drug delivery system, with a special focus on the MWCNTs surface functionalization (FA-PEG bis-amine functionalized, carboxylated MWCNTs). In vitro release of 5-fluorouracil (5-FU) was studied at pH 7.4 phosphate buffer and 5.5 acetate buffer, which displayed initial faster followed by sustained release up to 900 min. Further, 5-FU/FA-PEG bis amine-MWCNTs was found to be long circulating, prolonged half-life and increased drug accumulation in target tissue.

The application of susceptibility-weighted MRI in pre-interventional evaluation of intracranial dural arteriovenous fistulas.

BACKGROUND AND PURPOSE: Detection and characterization of intracranial dural arteriovenous fistula (DAVF) is important to plan appropriate therapeutic management. The aim of this study was to analyze the utility of susceptibility-weighted MRI (SWI) in the pre-therapeutic assessment of DAVF in comparison with gold standard digital subtraction angiography (DSA). MATERIALS AND METHODS: Prospectively, 26 patients with DAVFs underwent a thorough clinical examination and MRI including SWI followed by cerebral DSA. Two observers blinded to the DSA findings evaluated conventional MRI and SWI images and identified the fistulous area (FA), cortical venous reflux (CVR), and cortical venous ectasia (CVE) and compared these observations with the DSA findings documented by a third observer. RESULTS: Aggressive clinical symptoms were observed in 31% of patients and benign features were noted in 69% of DAVFs. Conventional MRI could identify the FA in only 27% of patients. SWI accurately located 75% of all the FAs in 23 patients. However, SWI failed to identify DAVFs in three patients. CVR was detected in 89.6% of all aggressive DAVFs. The accuracy of SWI to identify CVE was 100% and the extent and degree correlated with DSA observations. CONCLUSIONS: SWI is a reliable non-invasive tool for the localization and characterization of DAVFs and is superior to conventional MRI in the evaluation of DAVFs. This sequence can demonstrate underlying cerebral hemodynamic stresses with a high degree of accuracy and provide valuable pre-therapeutic information.

Radiological evaluation of sphenozygomatic suture fixation for restoration of orbital volume: A retrospective study.

PURPOSE: Lateral displacement of fracture zygomaticomaxillary complex (ZMC) can cause significant increase in orbital volume leading to enophthalmos. The aim of this study was to radiologically evaluate the efficacy of sphenozygomatic (SZ) suture fixation for restoration of orbital volume after elevation of the temporalis in cases of fracture ZMC where the fixation of zygomatic arch (ZA) was deemed necessary through latero-posterior approach. MATERIALS & METHODS: 43 operated cases of fracture ZMC using 4-point fixation were divided into two groups. Group I (n = 24) cases had undergone reduction and fixation of SZ suture as fourth point of fixation by elevating temporalis muscle using hemicoronal approach. Group II (n = 19) cases had undergone reduction and fixation of Infraorbital (IO) rim as fourth point of fixation using preseptal transconjunctival approach. Both the groups were analyzed separately and compared for restoring the increased orbital volume on CT. RESULTS: Difference in the pre-surgical orbital volume of both the groups was found to be statistically insignificant [p = .678]. In group I, the average bony orbital volume significantly reduced by 3.6 cc from 25.5 cc to 21.9 cc [p = .000] post-surgically. In group II, the average bony orbital volume reduced by 1.5 cc from 25.6 cc to 24.1 cc post-surgically There was a significant difference in the reduction of the increased orbital volume among the 2 groups (Group I: 3.6 cc, group II: 1.5 cc). The amount of reduction was more and statistically significant [p = .000] in the group I than group II. CONCLUSION: SZ suture fixation is reliable in reducing fractures ZMC and restoring the increased orbital volume where the fixation of zygomatic arch (ZA) was deemed necessary through latero-posterior approach.

Luteinizing hormone-releasing hormone peptide tethered nanoparticulate system for enhanced antitumoral efficacy of paclitaxel.

AIM: Paclitaxel (PTX) is an effective anticancer agent used in the therapy of a wide variety of cancers. However, the drug is difficult to formulate due to its low solubility, and therefore, it is administered under slow infusion with castor oil/ethanol solution as surfactant that causes serious side effects. This investigation investigates leutinizing hormone releasing hormone (LHRH)-tethered nanparticulate system as modality for cancer-specific delivery of PTX and therefore minimizing the adverse effects. MATERIALS & METHODS: LHRH-tethered poly(lactic-co-glycolic acid) copolymer with poly ethylene glycol side chain was synthesized, characterized and employed to formulate PTX-loaded nanoparticulate system. RESULTS & CONCLUSION: The developed nanoparticulate appears to be proficient in carrying as well as targeted delivery of PTX with improved therapeutic efficacy and better safety.

Effect of functionalization on drug delivery potential of carbon nanotubes.

The main aim of the present investigation was to explore the effect of functionalization on drug delivery potential of carbon nanotubes (CNTs) and to compare the in vitro and in vivo cancer targeting potential of doxorubicin HCL (DOX)-loaded ox-/multi-walled CNTs (MWCNTs), DOX-loaded PEG-MWCNTs and DOX-loaded FA-PEG-MWCNTs. The DOX/PEG-FA-MWCNTs showed enhanced cytotoxicity and were most preferentially taken up by the cancerous cells. The obtained results also support the extended resistance time and sustained release profile of drug-loaded surface-engineered MWCNTs. Overall, we concluded that the developed MWCNTs nanoformulations have higher cancer targeting potential.

Lyophilized mucoadhesive-dendrimer enclosed matrix tablet for extended oral delivery of albendazole.

Dendrimers are multifunctional carriers widely employed for delivering drugs in a variety of disease conditions including HIV/AIDS and cancer. Albendazole (ABZ) is a commonly used anthelmintic drug in human as well as veterinary medicine. In this investigation, ABZ was formulated as a "muco-dendrimer" based sustained released tablet. The mucoadhesive complex was synthesized by anchoring chitosan to fifth generation PPI dendrimer (Muco-PPI) and characterized by UV, FTIR, (1)H NMR spectroscopy and electron microscopy. ABZ was entrapped inside Muco-PPI followed by lyophilization and tableting as matrix tablet. A half-life (t1/2) of 8.06±0.15, 8.17±0.47, 11.04±0.73, 11.49±0.92, 12.52±1.04 and 16.9±1.18h was noted for ABZ (free drug), conventional ABZ tablet (F1), conventional ABZ matrix tablet (F2), PPI-ABZ complex, PPI-ABZ matrix tablet (F3) and Muco-PPI-ABZ matrix tablet (F4), respectively. Thus the novel mucoadhesive-PPI based formulation of ABZ (F4) increased the t1/2 of ABZ significantly by almost twofold as compared to the administration of free drug. The in vivo drug release data showed that the Muco-PPI based formulations have a significantly higher Cmax (2.40±0.02µg/mL) compared with orally administered free ABZ (0.19±0.07µg/mL) as well as conventional tablet (0.20±0.05µg/mL). In addition, the Muco-PPI-ABZ matrix tablet displayed increased mean residence time (MRT) and is therefore a potential candidate to appreciably improve the pharmacokinetic profile of ABZ.

Design of multifunctional nanocarriers for delivery of anti-cancer therapy.

Chemotherapy is the major and most widely used therapeutic strategy for the treatment of a wide variety of cancers. The non-specific/non-targeted drug delivery in chemotherapy leads to undesired side effects in normal and healthy tissues, and insufficient dosages to kill cancerous cells. Now-a-days, smart and intelligent multifunctional targeted nanomedicines based on various nanocarriers (dendrimers, carbon nanotubes, graphene, nanoparticles, quantum dots, self-emuslifying lipidic systems and carbon nanohorns etc) are being investigated promisingly in cancer treatment. In this article, we review the role of smart and intellegent multifucntional nanocarriers in delivery of chemotherapeutic agents with the aim to develop promising treatment strategy to combat with one of the killer of man kind i.e. cancer.

Validating the anticancer potential of carbon nanotube-based therapeutics through cell line testing.

Recent years have witnessed the booming development of carbon nanotubes (CNTs) and their composites in biological and medicine. By virtue of their unique physicochemical properties, CNTs have emerged as potential tools in biomedical applications as a result of their development as safe, effective nanomedicines. Diverse cell lines have been shown to be best-fit experimental models for evaluating the pharmacokinetic parameters, cell viability, and cytotoxicity of CNTS, as well as their drug efficacy ex vivo, which can then be correlated with their in vivo performance. The biological activities and cytotoxic effects of CNTs are dependent on their surface chemistry, and how they are purified and functionalized. Here, we focus on aspects of CNTs including their functionalization, and their biomedical potential and limitations, emphasizing the toxicological aspects of functionalized CNTs using various cell lines. The outlook for CNT-based nanomedicine, particularly in cancer treatment, is fascinating and encouraging. In vitro cell line data can assist the selection of specific cancer cell lines for the evaluation of anticancer bioactive-loaded CNTs as a novel drug delivery tool in the diagnosis and treatment of cancer.

Surface-engineered dendrimeric nanoconjugates for macrophage-targeted delivery of amphotericin B: formulation development and in vitro and in vivo evaluation.

The present study aimed to develop an optimized dendrimeric delivery system for amphotericin B (AmB). Fifth-generation (5.0 G) poly(propylene imine) (PPI) dendrimers were synthesized, conjugated with mannose, and characterized by use of various analytical techniques, including Fourier transform infrared spectroscopy (FTIR), (1)H nuclear magnetic resonance ((1)H-NMR) spectroscopic analysis, and atomic force microscopy (AFM). Mannose-conjugated 5.0 G PPI (MPPI) dendrimers were loaded with AmB and evaluated for drug loading efficiency, in vitro drug release profile, stability, hemolytic toxicity to human erythrocytes, cytotoxicity to and cell uptake by J774A.1 macrophage cells, antiparasitic activity against intracellular Leishmania donovani amastigotes, in vivo pharmacokinetic and biodistribution profiles, drug localization index, toxicity, and antileishmanial activity. AFM showed the nanometric size of the MPPI dendrimers, with a nearly globular architecture. The conjugate showed a good entrapment efficiency for AmB, along with pH-sensitive drug release. Highly significant reductions in toxicity toward human erythrocytes and macrophage cells, without compromising the antiparasitic activity of AmB, were observed. The dendrimeric formulation of AmB showed a significant enhancement of the parasiticidal activity of AmB toward intramacrophagic L. donovani amastigotes. In the in vitro cell uptake studies, the formulation showed selectivity toward macrophages, with significant intracellular uptake. Further pharmacokinetic and organ distribution studies elucidated the controlled delivery behavior of the formulation. The drug localization index was found to increase significantly in macrophage-rich organs. In vivo studies showed a biocompatible behavior of MPPIA, with negligible toxicity even at higher doses, and promising antileishmanial activity. From the results, we concluded that surface-engineered dendrimers may serve as optimized delivery vehicles for AmB with enhanced activity and low or negligible toxicity.

Characterization and evaluation of amphotericin B loaded MDP conjugated poly(propylene imine) dendrimers.

This paper describes a novel strategy for targeted delivery of amphotericin B (AmB) to macrophages with muramyl dipeptide (MDP) conjugated multimeric poly(propyleneimine) (PPI) dendrimers. Synergistic antiparasitic activity due to immunostimulation by multimeric presentation of MDP on dendrimers was anticipated. MDP conjugated 5.0G PPI (MdPPI) dendrimers were synthesized and characterized. Therapeutic activity and toxicity of dendrimeric formulation of AmB (MdPPIA) were compared with marketed formulations of AmB. Highly significant (P<0.01) reduction in toxicity was observed in hemolytic toxicity and cytotoxicity studies in erythrocytes and J774A.1 macrophage cells, respectively. Formulation MdPPIA showed appreciable macrophage targeting potential and higher or equivalent antiparasitic activity against parasite infected macrophage cell lines and in vivo infection in Balb/c mice. These results suggest the developed MDP conjugated dendrimeric formulation of AmB as a promising immunostimulant targeted drug delivery system and a safer alternative to marketed formulations. From the clinical editor: Parasitic infections remain a significant issue in the clinical setting. The authors in this article studied the use of ligand anchored dendrimeric formulation of Amphotericin B to target infected macrophages and showed reduced toxicity, high anti-leishmanial activity. This may add another treatment option to available formulations in the future.

Effect of surface capping on targeting potential of folate decorated poly (propylene imine) dendrimers.

OBJECTIVE: The objective of the present investigation was to assess and compare the effect of surface capping by different groups (-OH, -COOH and -NH2) on tumor targeting potential of folate conjugated poly (propylene imine) (PPI) (F-PPI) dendrimers using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay. MATERIALS AND METHODS: The synthesized nanoconjugates (F-PPI, F-COOH-PPI, F-OH-PPI and F-CONH-PPI) were characterized by Fourier transform infrared spectroscopy (FT-IR), nuclear magnetic resonance ((1)H-NMR) and transmission electron microscopic (TEM) studies. The formulations were evaluated for drug entrapment, in vitro drug release and hemolytic toxicity, and cytotoxicity was evaluated on HeLa and SiHa cell line using MTT assay. RESULTS: In case of all surface capped formulation, Methotrexate (MTX) loading was found to increased; however MTX release rate was found to decrease as compared to unmodified formulation. Further, F-COOH-PPI displayed highest tumor targeting potential as compared to other formulations. This is the first study to explore the effect of surface capping on the targeting potential of folate-conjugated fifth generation (5.0 G) PPI dendrimer. CONCLUSIONS: In conclusion, the targeting potential of all the formulations (anticancer activity) for both HeLa and SiHa cells follows in the following order: F-COOH-PPI > F-OH-PPI > F-CONH-PPI > F-PPI.

Dendrimer, liposomes, carbon nanotubes and PLGA nanoparticles: one platform assessment of drug delivery potential.

Liposomes (LIP), nanoparticles (NP), dendrimers (DEN), and carbon nanotubes (CNTs), represent eminent classes of drug delivery devices. A study was carried out herewith by employing docetaxel (DTX) as model drug to assess their comparative drug delivery potentials. Under optimized conditions, highest entrapment of DTX was observed in CNT-based formulation (DTX-CNTs, 74.70 ± 4.9%) followed by nanoparticles (DTX-NP, 62.34 ± 1.5%), liposome (49.2 ± 1.51%), and dendrimers (28.26 ± 1.74%). All the formulations were found to be of nanometric size. In vitro release studies were carried out in PBS (pH 7.0 and 4.0), wherein all the formulations showed biphasic release pattern. Cytotoxicity assay in human cervical cancer SiHa cells inferred lowest IC50 value of 1,235.09 ± 41.93 nM with DTX-CNTs, followed by DTX-DEN, DTX-LIP, DTX-NP with IC50 values of 1,571.22 ± 151.27, 1,653.98 ± 72.89, 1,922.75 ± 75.15 nM, respectively. Plain DTX showed higher hemolytic toxicity of 22.48 ± 0.94%, however loading of DTX inside nanocarriers drastically reduced its hemolytic toxicity (DTX-DEN, 17.22 ± 0.48%; DTX-LIP, 4.13 ± 0.19%; DTX-NP, 6.43 ± 0.44%; DTX-CNTs, 14.87 ± 1.69%).

Fucosylated multiwalled carbon nanotubes for Kupffer cells targeting for the treatment of cytokine-induced liver damage.

PURPOSE: To develop, characterize and exploring the sulfasalazine loaded fucoyslated multi walled carbon nanotubes for Kupffer cell targeting for effective management of cytokine-induce liver damage. METHODS: Sulfasalazine was loaded into the fucosylated MWCNTs after subsequential functionalization (carboxylation, acylation and amidation) using dialysis membrane technique. The in vitro, in vivo studies were performed on macrophages J 774 cell line for Kupffer cells targeting for the treatment of cytokine-induced liver damage. RESULTS: The loading of SSZ into SSZ-FUCO-MWCNTs was 87.77 ± 0.11% (n = 3). Sustained release was obtained from SSZ-FUCO-MWCNTs, with 89.12 ± 0.71% of SSZ released into medium at 48th hr. SSZ-FUCO-MWCNTs showed the 9.0 ± 0.23% hemolysis was drastically reduced from 21.62 ± 0.24% SSZMWCNTs 21.62 ± 0.24%. In SRB assay, SSZ-FUCO-MWCNTs showed more cytotoxicity than raw and SSZ-MWCNTs. In cytokine assay, SSZ- FUCO-MWCNTs exhibited significantly higher inhibition of IL-12 p40 secretion. In Western blot assay, SSZ-FUCO-MWCNTs significantly inhibit NF-κB activation. CONCLUSION: The results suggested that the SSZ-FUCO-MWCNTs may be useful nano-carriers for targeted delivery to Kupffer cells in the treatment of cytokine-induced liver damage.