Iliyas Khan

Polymeric Micelles: Recent Advancements in the Delivery of Anticancer Drugs

Nanotechnology, in health and medicine, extensively improves the safety and efficacy of different therapeutic agents, particularly the aspects related to drug delivery and targeting. Among various nano-carriers, polymer based macromolecular approaches have resulted in improved drug delivery for the diseases like cancers, diabetes, autoimmune disorders and many more. Polymeric micelles consisting of hydrophilic exterior and hydrophobic core have established a record of anticancer drug delivery from the laboratory to commercial reality. The nanometric size, tailor made functionality, multiple choices of polymeric micelle synthesis and stability are the unique properties, which have attracted scientists and researchers around the world to work upon in this opportunistic drug carrier. The capability of polymeric micelles as nano-carriers are nowhere less significant than nanoparticles, liposomes and other nanocarriers, as per as the commercial feasibility and presence is concerned. In fact polymeric micelles are among the most extensively studied delivery platforms for the effective treatment of different cancers as well as non-cancerous disorders. The present review highlights the sequential and recent developments in the design, synthesis, characterization and evaluation of polymeric micelles to achieve the effective anticancer drug delivery. The future possibilities and clinical outcome have also been discussed, briefly.

Dendrimers as an Effective Nanocarrier in Cardiovascular Disease.

In the last two decades, dendrimers have proven their capabilities in drug delivery, physical stabilization of the drug, solubility enhancement of the poorly soluble drugs and gene delivery. Several key features of dendrimers such as excellent control over molecular structure, nanoscopic size, availability of multiple functional groups at the periphery and narrow polydispersity index distinguish them as a superior choice over available polymers. The diversity of bio-actives loaded in dendrimers due to covalent and non-covalent interactions, such as hydrogen bonding and hydrophobic interaction contribute to the physical forces for binding of bioactives. The key advantage of drug-loaded dendrimers is the delayed and sustained-release of bioactives because of the encapsulation of the drug in the hydrophobic cavities of the dendrimer that acts as a sink to retain the drug molecules for extended duration. Because of these features researchers are particularly excited about the potential application of dendrimers as a versatile carrier for drug delivery. Collectively, this review focuses on detailed note on the delivery and improved solubility of poorly soluble anti-cardiovascular bioactives, nitric oxide (NO) donor for anti-thrombosis, gene delivery and delivery of receptor agonists for cardio-protective action of the receptors using dendrimers.

PLGA Nanoparticles and Their Versatile Role in Anticancer Drug Delivery

Nanotechnological advancement has become a key standard for the diagnosis and treatment of several complex disorders such as cancer by utilizing the enhanced permeability and retention effect and tumor-specific targeting. Synthesis and designing the formulation of active agents in terms of their efficient delivery is of prime importance for healthcare. The use of nanocarriers has resolved the undesirable characteristics of anticancer drugs such as low solubility and poor permeability in cells. Several types of nanoparticles (NPs) have been designed with the use of various polymers along or devoid of surface engineering for targeting tumor cells. All NPs include polymers in their framework and, of these, polylactide-co-glycolide (PLGA) is biodegradable and Food and Drug Administration approved for human use. PLGA has been used extensively in the development of NPs for anticancer drug delivery. The extensive use of PLGA NPs is promising for cancer therapy, with higher efficiency and less adverse effects. The present review focused on recent developments regarding PLGA NPs, the methods used for their preparation, their characterization, and their utility in the delivery of chemotherapeutic agents.

Enhanced apoptotic and anticancer potential of paclitaxel loaded biodegradable nanoparticles based on chitosan

Taxanes have established and proven effectivity against different types of cancers; in particular breast cancers. However, the high hemolytic toxicity and hydrophobic nature of paclitaxel and docetaxel have always posed challenges to achieve safe and effective delivery. Use of bio-degradable materials with an added advantage of nanotechnology could possibly improve the condition so as to achieve better and safe delivery. In the present study paclitaxel loaded chitosan nanoparticles were formulated and optimized using simple w/o nanoemulsion technique. The observed average size, pdi, zeta potential, entrapment efficiency and drug loading for the optimized paclitaxel loaded chitosan nanoparticle formulation (PTX-CS-NP-10) was 226.7±0.70nm, 0.345±0.039, 37.4±0.77mV, 79.24±2.95% and 11.57±0.81%; respectively. Nanoparticles were characterized further for size by Transmission Electron Microscopy (TEM). In vitro release studies exhibited sustained release pattern and more than 60% release was observed within 24h. Enhanced in vitro anticancer activity was observed as a result of MTT assay against triple negative MDA-MB-231 breast cancer cell lines. The observed IC50 values obtained for PTX-CS-NP-10 was 9.36±1.13μM and was almost 1.6 folds (p<0.05) less than the pure drug. Similarly, PTX-CS-NP-10 were extremely biocompatible and safe as observed for haemolytic toxicity which was almost 4 folds less (p<0.05) than the naïve drug. Anticancer activity was further evaluated using flow cytometry for apoptosis. Cell apoptosis study revealed that PTX-CS-NP-10 treatment resulted into enhanced (almost double) late cell apoptosis than naïve paclitaxel. Hence the developed nanoparticulate formulation not only reduced the overall toxicity but also resulted into improved anticancer efficacy of paclitaxel. It can be concluded that a robust, stable and comparatively safe nanoformulation of paclitaxel was developed, characterized and evaluated.

Biodegradable nano-architectural PEGylated approach for the improved stability and anticancer efficacy of bendamustine.

Bendamustine is a drug of choice for the treatment of several cancers including non- Hodgkin lymphoma (NHL) and Chronic Lymphocytic Leukemia (CLL). The unstable nature of the drug, however, offers a major obstacle in its effective formulation development. The present study was aimed to achieve improved stability and efficacy of bendamustine via co-polymeric PEG-PLGA nanoparticulate approach. PEG-PLGA co-polymeric conjugate was synthesized and characterized by FT-IR and 1H NMR spectroscopy. Bendamustine loaded nanoparticles (PLGA and PEG-PLGA) were prepared, optimized and characterized for size, zeta and electron microscopy (SEM and TEM). The average size, pdi (polydispersity index), zeta potential and entrapment efficiency for bendamustine loaded PEG-PLGA nanoparticles (PPBNP 15) was 297.3±2.055nm, 0.256±0.012, -6.62±0.081mV and 52.30±3.66%, respectively. The in vitro release studies displayed sustained release nature of bendamustine. The Krosmeyer-Peppas model was the best fit model as a result of kinetic modelling for in vitro release. The ex vivo hemolytic toxicity of the PPBNP 15 was significantly less (approx. 11%; 4 folds) compared to pure drug (p<0.05). The cytotoxicity study showed significantly higher anticancer activity against MCF-7, T47D and PC-3 cells (p<0.05) compared to naïve bendamustine. The developed biodegradable nanoparticles improved the stability of bendamustine and were equally stable, less toxic and highly effective against different cancerous cells.

Polypropyleneimine and polyamidoamine dendrimer mediated enhanced solubilization of bortezomib: Comparison and evaluation of mechanistic aspects by thermodynamics and molecular simulations

Bortezomib (BTZ) is the first proteasome inhibitor approved by the US-FDA is majorly used for the treatment of newly diagnosed and relapsed multiple myeloma including mantle cell lymphoma. BTZ is hydrophobic in nature and is a major cause for its minimal presence as marketed formulations. The present study reports the design, development and characterization of dendrimer based formulation for the improved solubility and effectivity of bortezomib. The study also equally focuses on the mechanistic elucidation of solubilization by two types of dendrimers i.e. fourth generation of poly (amidoamine) dendrimers (G4-PAMAM-NH2) and fifth generation of poly (propylene) imine dendrimers (G5-PPI-NH2). It was observed that aqueous solubility of BTZ was concentration and pH dependent. At 2mM G5-PPI-NH2 concentration, the fold increase in bortezomib solubility was 1152.63 times in water, while approximately 3426.69 folds increase in solubility was observed at pH10.0, respectively (p<0.05). The solubility of the drug was increased to a greater extent with G5-PPI-NH2 dendrimers because it has more hydrophobic interior than G4-PAMAM-NH2 dendrimers. The release of BTZ from G5-PPI-NH2 complex was comparatively slower than G4-PAMAM-NH2. The thermodynamic treatment of data proved that dendrimer drug complexes were stable at all pH with values of ΔG always negative. The experimental findings were also proven by molecular simulation studies and by calculating RMSD and intermolecular hydrogen bonding through Schrodinger software. It was concluded that PPI dendrimers were able to solubilize the drug more effectively than PAMAM dendrimers through electrostatic interactions.

Bendamustine–PAMAM Conjugates for Improved Apoptosis, Efficacy, and in Vivo Pharmacokinetics: A Sustainable Delivery Tactic

Successful delivery of a chemotherapeutic agent like bendamustine still remains a challenge in clinical conditions like chronic lymphatic leukemia (CLL), non-Hodgkin lymphoma (NHL), and multiple myeloma. We have conjugated bendamustine to polyamidoamine (PAMAM) dendrimers after conjugating with N-(hydroxyethyl)maleimide (spacer) via an ester bond. The particle size of PAMAM-bendamustine conjugate was 49.8 ± 2.5 nm. In vitro drug release resulted in sustained release with improved solution stability of drug up to 72 h. In a 24 h cytotoxicity study by MTT assay against human monoblastic leukemia cells (THP-1), the IC50 value for PAMAM-bendamustine was 32.1 ± 4.8 μM compared to 50.42 ± 3.4 μM and 2303 ± 106.5 μM for bendamustine and PAMAM dendrimer, respectively. Significantly higher cell uptake and apoptosis were observed in THP-1 cells by PAMAM-bendamustine conjugate which was confirmed by flow cytometry and confocal laser scanning microscopy. Preliminary in vivo studies undertaken included pharmacokinetics studies, organ distribution studies, and tumor inhibition studies. In healthy Wistar rat model (1CBM IV push model), the pharmacokinetic studies revealed that bioavailability and t1/2 increased significantly, i.e., almost 8.5-fold (193.8 ± 1.116 vs 22.8 ± 0.158 μg mL-1/h) and 5.1-fold (0.75 ± 0.005 vs 3.85 ± 0.015 h), respectively, for PAMAM-bendamustine conjugate compared to pure bendamustine ( p < 0.05), however, clearance and volume of distribution were found to be decreased compared to those of free drug. The study suggests that PAMAM-bendamustine conjugate was not only stable for the longer period but also least toxic and highly taken up by THP-1 cells to exert an anticancer effect at the reduced dose. Tumor inhibition and biodistribution studies in tumor-bearing BALB/c mice revealed that PAMAM-bendamustine conjugate was more effective than the pure drug and showed higher accumulation in the tumor.

Polymeric Nanocarriers: A New Horizon for the Effective Management of Breast Cancer

BACKGROUND Delivery of chemotherapeutic drugs for the diagnosis and treatment of cancer is becoming advanced day by day. However, the challenge of the effective delivery system still does exist. In various types of cancers, breast cancer is the most commonly diagnosed cancer among women. Breast cancer is a combination of different diseases. It cannot be considered as only one entity because there are many specific patient factors, which are involved in the development of this disease. Nanotechnology has opened a new area in the effective treatment of breast cancer due to the several benefits offered by this technology. METHODS Polymeric nanocarriers are among one of the effective delivery systems, which has given promising results in the treatment of breast cancers. Nanocarriers does exert their anticancer effect either through active or passive targeting mode. RESULTS The use of nanocarriers has been resolute about the adverse effects of chemotherapeutic drugs such as poor solubility and less penetrability in tumor cells. CONCLUSION The present review is focused on recent developments regarding polymeric nanocarriers, such as polymeric micelles, polymeric nanoparticles, dendrimers, liposomes, nanoshells, fullerenes, carbon nanotubes (CNT) and quantum dots, etc. for their recent advancements in breast cancer therapy.

Polymeric Nanoparticles in Targeting and Delivery of Drugs

In the recent two or three decades, polymeric nanoparticles (PNPs) have continuously played a pivotal role in various fields such as electronics, sensors, photonics, biotechnology, and nanomedicines. PNPs have attained much popularity due to their unique properties like biodegradability, biocompatibility, and biomimetic characteristics. A variety of techniques are available to produce PNPs such as solvent evaporation, supercritical fluid technology, microemulsion, salting-out, dialysis, miniemulsion, and interfacial polymerization and surfactant-free emulsion also distinguish from other nanocarriers. This chapter highlights and discusses the general description of PNPs, their methods of preparation, clinical applications, and their amazing role in targeted drug delivery.

Oral drug delivery potential of dendrimers

Oral route is among the most common routes for drug administration due to its own merits and ease. The continuous advancement of drug delivery in the recent past, nanotherapeutics have attracted researchers as a novel, safer, and efficient technology for effective drug delivery. However, in most instances the nanomedicine-based approaches have been following the parenteral route of drug administration. Several nanocarriers have been reported in the last few decades for the improved delivery of drugs. Most of these drug carriers have frequently been reported as delivering through routes other than oral. Recent updates, however, say that these carriers have immense potential to be delivered via oral routes as well. In this regard, dendrimers with three-dimensional polymeric architecture, tuneable functionality, and nanometric size are better suited for oral delivery. Dendrimers are reported as carriers for solubility enhancement, for therapeutic delivery, to reduce the cytotoxicity of the drug, to enhance stability of the drug, and for increasing bioavailability of drugs in oral administration. Though there is a scarcity of the oral delivery of drugs using dendrimers, many drugs, such as propranolol, triclosan, nitric oxide, clotrimazole, ketoconazole, silicone and so on have been successfully delivered using dendrimers. The present chapter highlights the potential application of dendrimers in oral drug delivery.