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RNAi-combined nano-chemotherapeutics to tackle resistant tumors

Tekade RK, Tekade M, Kesharwani P

Drug Discov Today, 2016 Jul 2.
PMID: 27380716 DOI: 10.1016/j.drudis.2016.06.029

The merger of nanotechnology and combination chemotherapy has shown notable promise in the therapy of resistant tumors. The latest scientific attention encompasses the engagement of anticancer drugs in combination with small interfering (si)RNAs, such as VEGF, XLAP, PGP, MRP-1, BCL-2 and cMyc, to name but a few. siRNAs have shown immense promise to knockout drug resistance genes as well as to recover the sensitivity of resistant tumors to anticancer therapy. The nanotechnology approach could also protect siRNA against RNAse degradation as well as prevent off-target effects. In this article, we discuss the approaches that have been used to deliver of siRNA in combination with chemotherapeutic drugs to treat resistant tumors. We also discuss the stipulations that must be considered in formulating a nanotechnology-assisted siRNA-drug cancer therapy.
Nanocarriers Assisted siRNA Gene Therapy for the Management of Cardiovascular Disorders

Maheshwari R, Tekade M, Sharma PA, Tekade RK

Curr Pharm Des, 2015;21(30):4427-40.
PMID: 26471319

Cardiovascular diseases (CVDs), primarily myocardial infarction (MI), atherosclerosis, hypertension and congestive heart failure symbolize the foremost cause of death in almost all parts of the world. Besides the traditional therapeutic approaches for the management of CVDs, newer innovative strategies are also emerging on the horizon. Recently, gene silencing via small interfering RNA (siRNA) is one of the hot topics amongst various strategies involved in the management of CVDs. The siRNA mechanism involves natural catalytic processes to silence pathological genes that are overexpressed in a particular disease. Also the versatility of gene expression by siRNA deciphers a prospective tactic to down-regulate diseases associated gene, protein or receptor existing on a specific disease target. This article reviews the application of siRNA against CVDs with special emphasis on gene targets in combination with delivery systems such as cationic hydrogels, polyplexes, peptides, liposomes and dendrimers.
Nanomaterial Based Approaches for the Diagnosis and Therapy of Cardiovascular Diseases

Sharma PA, Maheshwari R, Tekade M, Tekade RK

Curr Pharm Des, 2015;21(30):4465-78.
PMID: 26354926

The increasing prevalence and complexity of cardiovascular diseases demand innovative strategies for diagnostic and therapeutic applications to improve patient care/prognoses. Additionally, various factors constrain present cardiovascular therapies, including low aqueous drug solubility, early metabolism, short half-life and drug delivery limitations. The efficient treatment of cardiovascular diseases requires improvement of traditional drug delivery systems. This can be accomplished by using novel nanomaterial that can incorporate diverse bio-actives along with diagnostic agents in a single carrier, referred to as theranostics. This review discusses the state of the art in the applications to diagnosis and therapy of innovative, nanomaterial- based strategies such as lipid based carriers, nanocapsules, magnetic nanoparticles, gold nanoparticles, protein conjugated nanoparticles, dendrimers and carbon-based nanoformulations with a special emphasis on how they can contribute to improving the management of cardiovascular disease.
siRNA Therapy, Challenges and Underlying Perspectives of Dendrimer as Delivery Vector

Tekade RK, Maheshwari RG, Sharma PA, Tekade M, Chauhan AS

Curr Pharm Des, 2015;21(31):4614-36.
PMID: 26486147

siRNA technology presents a helpful means of gene silencing in mammalian cells. Advancement in the field includes enhanced attentiveness in the characterization of target and off-target effects employing suitable controls and gene expression microarrays. These will permit expansion in the measurement of single and multiple target combinations and also permit comprehensive efforts to understand mammalian cell processes. Another fact is that the delivery of siRNA requires the creation of a nanoparticulate vector with controlled structural geometry and surface modalities inside the targeted cells. On the other hand, dendrimers represent the class of carrier system where massive control over size, shape and physicochemical properties makes this delivery vector exceptional and favorable in genetic transfection applications. The siRNA therapeutics may be incorporated inside the geometry of the density controlled dendrimers with the option of engineering the structure to the specific needs of the genetic material and its indication. The existing reports on the siRNA carrying and deliverance potential of dendrimers clearly suggest the significance of this novel class of polymeric architecture and certainly elevate the futuristic use of this highly branched vector as genetic material delivery system.
The use of nanoscaffolds and dendrimers in tissue engineering

Gorain B, Tekade M, Kesharwani P, Iyer AK, Kalia K, Tekade RK

Drug Discov Today, 2017 04;22(4):652-664.
PMID: 28219742 DOI: 10.1016/j.drudis.2016.12.007

To avoid tissue rejection during organ transplantation, research has focused on the use of tissue engineering to regenerate required tissues or organs for patients. The biomedical applications of hyperbranched, multivalent, structurally uniform, biocompatible dendrimers in tissue engineering include the mimicking of natural extracellular matrices (ECMs) in the 3D microenvironment. Dendrimers are unimolecular architects that can incorporate a variety of biological and/or chemical substances in a 3D architecture to actively support the scaffold microenvironment during cell growth. Here, we review the use of dendritic delivery systems in tissue engineering. We discuss the available literature, highlighting the 3D architecture and preparation of these nanoscaffolds, and also review challenges to, and advances in, the use dendrimers in tissue engineering. Advances in the manufacturing of dendritic nanoparticles and scaffold architectures have resulted in the successful incorporation of dendritic scaffolds in tissue engineering.
Fulltext Force degradation behavior of glucocorticoid deflazacort by UPLC: isolation, identification and characterization of degradant by FTIR, NMR and mass analysis

Deshmukh R, Sharma L, Tekade M, Kesharwani P, Trivedi P, Tekade RK

J Biomed Res, 2016 Mar;30(2):149-161.
PMID: 28276670 DOI: 10.7555/JBR.30.20150074

In this investigation, sensitive and reproducible methods are described for quantitative determination of deflazacort in the presence of its degradation product. The method was based on high performance liquid chromatography of the drug from its degradation product on reverse phase using Acquity UPLC BEH C18 columns (1.7 µm, 2.1 mm × 150 mm) using acetonitrile and water (40:60 V/V) at a flow rate of 0.2 mL/minute in UPLC. UV detection was performed at 240.1 nm. Deflazacort was subjected to oxidative, acid, base, hydrolytic, thermal and photolytic degradation. The drug was found to be stable in water and thermal stress, as well as under neutral stress conditions. However, forced-degradation study performed on deflazacort showed that the drug degraded under alkaline, acid and photolytic stress. The degradation products were well resolved from the main peak, which proved the stability-indicating power of the method. The developed method was validated as per ICH guidelines with respect to accuracy, linearity, limit of detection, limit of quantification, accuracy, precision and robustness, selectivity and specificity. Apart from the aforementioned, the results of the present study also emphasize the importance of isolation characterization and identification of degradant. Hence, an attempt was made to identify the degradants in deflazacort. One of the degradation products of deflazacort was isolated and identified by the FTIR, NMR and LC-MS study.
Recent Advances in Oncological Submissions of Dendrimer

Soni N, Tekade M, Kesharwani P, Bhattacharya P, Maheshwari R, Dua K, et al.

Curr Pharm Des, 2017 08 30;23(21):3084-3098.
PMID: 28356042 DOI: 10.2174/1381612823666170329150201

BACKGROUND: Disseminated metastatic cancer requires insistent management owing to its reduced responsiveness for chemotherapeutic agents, toxicity to normal cells consequently lower survival rate and hampered quality of life of patients.
METHODS: Dendrimer mediated cancer therapy is advantageous over conventional chemotherapy, radiotherapy and surgical resection due to reduced systemic toxicity, and molecular level cell injury to cancerous mass, for an appreciable survival of the subject. Recently used dendrimer mediated nanotechnology for oncology aims to conquer these challenges. Dendrimers based nano-constructs are having architectures comparable to that of biological vesicles present in the human body.
RESULTS: Operating with dendrimer technology, proffers the exclusive and novel strategies with numerous applications in cancer management involving diagnostics, therapeutics, imaging, and prognostics by sub-molecular interactions. Dendrimers are designed to acquire the benefits of the malignant tumor morphology and characteristics, i.e. leaky vasculature of tumor, expression of specific cell surface antigen, and rapid proliferation.
CONCLUSION: Dendrimers mediated targeted therapy recommends innovatory function equally in diagnostics (imaging, immune-detection) as well as chemotherapy. Currently, dendrimers as nanomedicine has offered a strong assurance and advancement in drastically varying approaches towards cancer imaging and treatment. The present review discusses different approaches for cancer diagnosis and treatment such as, targeted and control therapy, photodynamic therapy, photo-thermal therapy, gene therapy, antiangiogenics therapy, radiotherapy etc.
Advanced nanoscale carrier-based approaches to overcome biopharmaceutical issues associated with anticancer drug 'Etoposide'

Choudhury H, Maheshwari R, Pandey M, Tekade M, Gorain B, Tekade RK

Mater Sci Eng C Mater Biol Appl, 2020 Jan;106:110275.
PMID: 31753398 DOI: 10.1016/j.msec.2019.110275

Etoposide (ETS), topoisomerase-II inhibitor, is a first-line anticancer therapeutics used in diverse cancer types. However, the therapeutic potential of this molecule has mainly impeded due to its detrimental toxicity profile, unfavorable rejection by the cancer cells due to P-glycoprotein (P-gp) efflux activity, and rapid hepatic clearance through extensive metabolism by Cytochrome-P450. To increase the therapeutic potency without significant adverse effects, the implication of novel ETS-nanoformulation strategies have recommended mainly. Nanomedicine based nanoformulation approaches based on nanoparticles (NPs), dendrimers, carbon-nanotubes (CNTs), liposomes, polymeric micelles, emulsions, dendrimers, solid-lipid NPs, etc offers immense potential opportunities to improve the therapeutic potential of pharmaceutically problematic drugs. This review provides an up-to-date argument on the work done in the field of nanomedicine to resolve pharmacokinetic and pharmacodynamic issues associated with ETS. The review also expounds the progress in regards to the regulatory, patenting and clinical trials related to the innovative formulation aspects of ETS.
Microsponge embedded tablet for sustained delivery of nifedipine

Rahul M, Piyoosh S, Tekade M, Atneriya U, Dua K, Hansbroe PM, et al.

Pharm Nanotechnol, 2017 09 21.
PMID: 28933273 DOI: 10.2174/2211738505666170921125549

BACKGROUND: Nifedipine is a potential therapeutic agent for the treatment of cardiovascular disturbances, although it suffers from short half-life (t1/2, 2 hr).
OBJECTIVE: To address the problem, we first prepared nifedipine loaded sustained releases microsponges and then formulated tablets for effective clinical application and patient compliance.
METHOD: Preparations of microsponges were carried out using different composition of nifedipine and polymer (1:1, 1:2 and 1:3 % molar ratio) using emulsion solvent diffusion technique.
RESULTS: The microsponges with molar ratio 1:3 (formulation code: MF-3) found optimized as revealed by analyzing surface morphology, better powder flow properties (angle of repose; 28.80 ± 0.9, Hausner ratio 1.15 ± 0.2, % compressibility 15.28 ± 0.5% and higher % drug content (80 ± 1.9 %). Different batches of tablets were then formulated incorporating MF-3 microsponges and different proportion (10-50 %) of microcrystalline cellulose and starch as additives. Among tablet formulations, batch composed of 48% of MF-3, 30% of MCC, 20 % of starch and 2 % of talc (TF-33), showed 92.73 ± 2.19 % drug release during 24 hr in vitro release study in comparison to other batches including commercial formulation which was found to be released completely in 20 hr. Further, stability analysis revealed good drug retention of loaded nifedipine as well as consistent in vitro release pattern over a period of 90 days at 40 ºC and 75% RH.
CONCLUSION: The microsponge tablet delivery system was found to be superior concerning the therapeutic advantage as well as manufacturing feasibility of nifedipine.
Fulltext Graphene-based hybrid nanoparticle of doxorubicin for cancer chemotherapy

SreeHarsha N, Maheshwari R, Al-Dhubiab BE, Tekade M, Sharma MC, Venugopala KN, et al.

Int J Nanomedicine, 2019;14:7419-7429.
PMID: 31686814 DOI: 10.2147/IJN.S211224

Background: Prostate cancer (PC) has the highest prevalence in men and accounts for a high rate of neoplasia-related death. Doxorubicin (DOX) is one of the most widely used anti-neoplastic drugs for prostate cancer among others. However, it has low specificity and many side effects and affects normal cells. More recently, there have been newly developed drug delivery tools which are graphene or graphene-based, used to increase the specificity of the delivered drug molecules. The graphene derivatives possess both π-π stacking and increased hydrophobicity, factors that increase the likelihood of drug delivery. Despite this, the hydrophilicity of graphene remains problematic, as it induced problems with stability. For this reason, the use of a chitosan coating remains one way to modify the surface features of graphene.
Method: In this investigation, a hybrid nanoparticle that consisted of a DOX-loaded reduced graphene oxide that is stabilized with chitosan (rGOD-HNP) was developed.
Result: The newly developed rGOD-HNP demonstrated high biocompatibility and efficiency in entrapping DOX (~65%) and releasing it in a controlled manner (~50% release in 48 h). Furthermore, it was also demonstrated that rGOD-HNP can intracellularly deliver DOX and more specifically in PC-3 prostate cancer cells.
Conclusion: This delivery tool offers a feasible and viable method to deliver DOX photo-thermally in the treatment of prostate cancer.