Sudipta Senapati

Layered double hydroxides as effective carrier for anticancer drugs and tailoring of release rate through interlayer anions

Hydrophobic anticancer drug, raloxifene hydrochloride (RH) is intercalated into a series of magnesium aluminum layered double hydroxides (LDHs) with various charge density anions through ion exchange technique for controlled drug delivery. The particle nature of the LDH in presence of drug is determined through electron microscopy and surface morphology. The release of drug from the RH intercalated LDHs was made very fast or sustained by altering the exchangeable anions followed by the modified Freundlich and parabolic diffusion models. The drug release rate is explained from the interactions between the drug and LDHs along with order-disorder structure of drug intercalated LDHs. Nitrate bound LDH exhibits greater interaction with drug and sustained drug delivery against the loosely interacted phosphate bound LDH-drug, which shows fast release. Cell viability through MTT assay suggests drug intercalated LDHs as better drug delivery vehicle for cancer cell line against poor bioavailability of the pure drug. In vivo study with mice indicates the differential tumor healing which becomes fast for greater drug release system but the body weight index clearly hints at damaged organ in the case of fast release system. Histopathological experiment confirms the damaged liver of the mice treated either with pure drug or phosphate bound LDH-drug, fast release system, vis-à-vis normal liver cell morphology for sluggish drug release system with steady healing rate of tumor. These observations clearly demonstrate that nitrate bound LDH nanoparticle is a potential drug delivery vehicle for anticancer drugs without any side effect.

Controlled drug delivery vehicles for cancer treatment and their performance

Although conventional chemotherapy has been successful to some extent, the main drawbacks of chemotherapy are its poor bioavailability, high-dose requirements, adverse side effects, low therapeutic indices, development of multiple drug resistance, and non-specific targeting. The main aim in the development of drug delivery vehicles is to successfully address these delivery-related problems and carry drugs to the desired sites of therapeutic action while reducing adverse side effects. In this review, we will discuss the different types of materials used as delivery vehicles for chemotherapeutic agents and their structural characteristics that improve the therapeutic efficacy of their drugs and will describe recent scientific advances in the area of chemotherapy, emphasizing challenges in cancer treatments.Cancer therapeutics: Special deliveryImproving the delivery of cancer therapies to tumor sites is crucial to reduce unwanted side effects and patient mortality rates. Pralay Maiti and colleagues at the Indian Institute of Technology in Varanasi, India, review the latest developments in drug delivery vehicles and treatment approaches designed to enhance the effectiveness of current cancer therapies. New nanoparticle-based carriers, hydrogels and hybrid materials that offer controlled and sustained drug release are showing great promise in animal models. Furthermore, materials that respond to stimuli such as heat, light, magnetic or electric fields are also being tested to aid target-specific drug delivery and, thus, avoid damage to healthy tissues. Although there are some challenges in translating these findings to the clinic, there is no doubt that technological advances are shaping better and safer treatment options.

Biodegradable poly(ε-caprolactone) as a controlled drug delivery vehicle of vancomycin for the treatment of MRSA infection

Biodegradable poly(ε-caprolactone) (PCL) is developed as a controlled drug delivery vehicle of vancomycin (VMC) with the advantage of avoiding a second surgery. The PCL-VMC hybrid, prepared through a solution route, is used as a delivery vehicle for vancomycin for controlling MRSA osteomyelitis as well as healing the cavity simultaneously in an experimental study. An in vitro study is conducted to optimize vancomycin impregnation in the PCL-VMC hybrid. An in vitro study on drug release from the hybrid material is investigated in phosphate buffer saline showing steady and sustained release of the drug. The release kinetics is fitted with several models and a non-Fickian nature is established following the Korsmeyer-Peppas model. Spectroscopic techniques and morphology observations reveal the cause of sustained release to be the strong interaction between the drug and the polymer. The results of the antibacterial assay show that the loading of vancomycin into the PCL matrix is able to maintain the activity of the pure drug. For the in vivo study, a unicortical defect is created in the metaphysis of the distal femur in rabbits. After contaminating the defect with MRSA, the 1st group of rabbits were treated with pure polymer, the 2nd group of rabbits were treated with normal saline (PBS), the 3rd group of rabbits were treated with pure VMC and in the last group of rabbits PCL-VMC was placed. Rabbits are assessed by clinical, radiological, histological, gross examination and bacterial load assays. Infection persisted throughout the period of study for both the pure polymer and PBS treated rabbits while rabbits treated with the PCL-VMC hybrid do not show any sign of infection. The VMC treated group rabbits show mild infection for the 1st week of the study; however, the infection becomes gradually more severe with time. Serial histology confirms the formation of new bone without any inflammation and necrosis for the rabbits treated with PCL-VMC. Importantly, the PCL-VMC hybrid bioadsorbs after delivery of the drug and thereby avoids the second surgery to remove the conventional implant.

Controlled drug release through regulated biodegradation of poly(lactic acid) using inorganic salts

Biodegradation rate of poly(lactic acid) (PLA) has been regulated, both increase and decrease with respect to the biodegradation of pure PLA, by embedding meager amount of inorganic salts in polymer matrix. Biodegradation is performed in enzyme medium on suspension and film and the extent of biodegradation is measured through spectroscopic technique which is also verified by weight loss measurement. Media pH has been controlled using trace amount of inorganic salt which eventually control the biodegradation of PLA. High performance liquid chromatography confirms the hydrolytic degradation of PLA to its monomer/oligomer. Induced pH by metal salts show maximum degradation at alkaline range (with calcium salt) while inhibition is observed in acidic medium (with iron salt). The pH of media changes the conformation of enzyme which in turn regulate the rate of biodegradation. Thermal degradation and increment of modulus indicate improvement in thermo-mechanical properties of PLA in presence of inorganic salts. Functional stability of enzyme with metal salts corresponding to acidic and alkaline pH has been established through a model to explain the conformational changes of the active sites of enzyme at varying pH influencing the rate of hydrolysis leading to regulated biodegradation of PLA. The tuned biodegradation has been applied for the controlled release of drug from the polymer matrix (both sustained and enhanced cumulative release as compared to pure polymer). The cell proliferation and adhesion are influenced by the acidic and basic nature of polymeric material tuned by two different inorganic salts showing better adhesion and proliferation in calcium based composite and, therefore, suggest biological use of these composites in biomedical applications.

A polyurethane–chitosan brush as an injectable hydrogel for controlled drug delivery and tissue engineering

Hydrogels and porous lyophilized hydrogels have been designed using a polyurethane brush with a chitosan backbone through grafting. The degree of substitution of grafting has been varied for controlled properties and has been confirmed by 13C NMR, FTIR and UV-vis measurements. Surface modification of chitosan has been done to check the hydrophilic–hydrophobic balance which is reflected in their swelling behavior and contact angle. Porous interconnected three dimensional network structures with controlled size are observed by using a scanning electron microscope. Hydrogels or lyophilized hydrogels have sufficient mechanical strength and the brush like structure helps increase the fluidity as measured from the lesser viscosity under oscillatory shear as compared to pure chitosan and thereby the brush acts like a slipping agent. Sustained drug release is achieved using a brush copolymer as opposed to burst release noticed in pure chitosan. A controlled drug release phenomenon has been modeled both for hydrogels and lyophilized hydrogels following the Fickian diffusion (n < 0.45). Excellent cytocompatibility of the brush copolymer has been verified through cell line studies using mouse embryonic fibroblast cells. Interestingly, the cells grow nicely within the pores of a graft copolymer while predominantly the usual cell growth on the surface is observed in the lyophilized hydrogel of chitosan indicating the effect of brush like modification on the chitosan backbone towards better cell proliferation. The developed brush copolymers have the ability to form hydrogels under physiological conditions at 37 °C through sol–gel transformation which makes them suitable to be used as injectable hydrogels as evidenced from the in vivo experiment using a rat model. Hence, the developed brush copolymers are promising as potential biomaterials for drug delivery and tissue engineering applications.

Engineered Cellular Uptake and Controlled Drug Delivery Using Two Dimensional Nanoparticle and Polymer for Cancer Treatment

Two major problems in chemotherapy, poor bioavailability of hydrophobic anticancer drug and its adverse side effects causing nausea, are taken into account by developing a sustained drug release vehicle along with enhanced bioavailability using two-dimensional layered double hydroxides (LDHs) with appropriate surface charge and its subsequent embedment in polymer matrix. A model hydrophobic anticancer drug, raloxifene hydrochloride (RH), is intercalated into a series of zinc iron LDHs with varying anion charge densities using an ion exchange technique. To achieve significant sustained delivery, drug-intercalated LDH is embedded in poly(ε-caprolactone) (PCL) matrix to develop intravenous administration and to improve the therapeutic index of the drug. The cause of sustained release is visualized from the strong interaction between LDH and drug, as measured through spectroscopic techniques, like X-ray photoelectron spectroscopy, infrared, UV-visible spectroscopy, and thermal measurement (depression of melting temperature and considerable reduction in heat of fusion), using differential scanning calorimeter, followed by delayed diffusion of drug from polymer matrix. Interestingly, polymer nanohybrid exhibits long-term and excellent in vitro antitumor efficacy as opposed to pure drug or drug-intercalated LDH or only drug embedded PCL (conventional drug delivery vehicle) as evident from cell viability and cell adhesion experiments prompting a model depicting greater killing efficiency (cellular uptake) of the delivery vehicle (polymer nanohybrid) controlled by its better cell adhesion as noticed through cellular uptake after tagging of fluorescence rhodamine B separately to drug and LDH. In vivo studies also confirm the sustained release of drug in the bloodstream of albino rats using polymer nanohybrid (novel drug delivery vehicle) along with a healthy liver vis-à-vis burst release using pure drug/drug-intercalated LDHs with considerable damaged liver.

A ‘turn-on’ fluorescent probe for lysosomal phosphatase: a comparative study for labeling of cancer cells

We have described the ability of a newly synthesized fluorescent probe (LP1) to detect phosphatase activity in lysosomes in cancer cells. Probe LP1 displayed a 33-fold fluorescence intensity enhancement at λem 532 nm in the presence of phosphatase in HEPES buffer (pH 4.5). The quantum yield of probe LP1 was increased by ∼21-fold upon exposure to phosphatase at acidic pH. The probe LP1 is highly chemoselective toward phosphatase (ALP/ACP) and is insensitive to interference by ubiquitous biological analytes. The high cell adhesion property and cell viability of LP1 indicate that LP1 is biocompatible and nontoxic; these two characteristic features make it a suitable candidate for phosphatase tracking in living cells. LP1 dose-dependent fluorescence images in living cells suggested that the expression of phosphatase in cancer cells (HeLa) is 2-fold higher as compared to the normal NIH-3T3 cells. The colocalization images confirmed that LP1 was exclusively localized in lysosomes. We envision that LP1 could be a potential tool in clinical diagnosis for discriminating cancer cells from normal cells depending on the expression of phosphatase in lysosomes.

Sustained release of herbal drugs using biodegradable scaffold for faster wound healing and better patient compliance

Electrospun scaffold has been developed using biodegradable polymer and age old herbal drug for efficient wound healing patch with much better patient compliance. Positively charged smaller particle size (40 nm) of the drug has been prepared for greater penetration through epidermal barrier to enhance the wound healing activity of drug. Controlled drug release has been understood in terms of interactions between the components through spectroscopic techniques and calorimetric studies. In-vivo study using albino rats shows better wound healing efficiency of scaffold in terms of higher wound area contraction, minimum inflammation, faster epithelialization and vascularization. Cellular studies also endorse the scaffold as better biomaterial. Clinical studies also demonstrate fast healing of different type of wounds in presence of all three wound dressing materials with histological evidences. The complete biodegradation of the patch confirms its green nature of the developed patch.