Anumita Chaudhury

Recent advances in lipid nanoparticle formulations with solid matrix for oral drug delivery.

Lipid nanoparticles based on solid matrix have emerged as potential drug carriers to improve gastrointestinal (GI) absorption and oral bioavailability of several drugs, especially lipophilic compounds. These formulations may also be used for sustained drug release. Solid lipid nanoparticle (SLN) and the newer generation lipid nanoparticle, nanostructured lipid carrier (NLC), have been studied for their capability as oral drug carriers. Biodegradable, biocompatible, and physiological lipids are generally used to prepare these nanoparticles. Hence, toxicity problems related with the polymeric nanoparticles can be minimized. Furthermore, stability of the formulations might increase than other liquid nano-carriers due to the solid matrix of these lipid nanoparticles. These nanoparticles can be produced by different formulation techniques. Scaling up of the production process from lab scale to industrial scale can be easily achieved. Reasonably high drug encapsulation efficiency of the nanoparticles was documented. Oral absorption and bioavailability of several drugs were improved after oral administration of the drug-loaded SLNs or NLCs. In this review, pros and cons, different formulation and characterization techniques, drug incorporation models, GI absorption and oral bioavailability enhancement mechanisms, stability and storage condition of the formulations, and recent advances in oral delivery of the lipid nanoparticles based on solid matrix will be discussed.

Recent advancement of chitosan-based nanoparticles for oral controlled delivery of insulin and other therapeutic agents.

Nanoparticles composed of naturally occurring biodegradable polymers have emerged as potential carriers of various therapeutic agents for controlled drug delivery through the oral route. Chitosan, a cationic polysaccharide, is one of such biodegradable polymers, which has been extensively exploited for the preparation of nanoparticles for oral controlled delivery of several therapeutic agents. In recent years, the area of focus has shifted from chitosan to chitosan derivatized polymers for the preparation of oral nanoparticles due to its vastly improved properties, such as better drug retention capability, improved permeation, enhanced mucoadhesion and sustained release of therapeutic agents. Chitosan derivatized polymers are primarily the quaternized chitosan derivatives, chitosan cyclodextrin complexes, thiolated chitosan, pegylated chitosan and chitosan combined with other peptides. The current review focuses on the recent advancements in the field of oral controlled release via chitosan nanoparticles and discusses about its in vitro and in vivo implications.

Preparation and evaluation of zinc–pectin–chitosan composite particles for drug delivery to the colon: Role of chitosan in modifying in vitro and in vivo drug release

Zinc-pectin-chitosan composite microparticles were designed and developed as colon-specific carrier. Resveratrol was used as model drug due to its potential activity on colon diseases. Formulations were produced by varying different formulation parameters (cross-linking pH, chitosan concentration, cross-linking time, molecular weight of chitosan, and drug concentration). Single-step formulation technique was compared with multi-step technique. Effect of these parameters was investigated on shape, size, weight, weight loss (WL), moisture content (MC), encapsulation efficiency (EE), drug loading (L), and drug release pattern of the microparticles. The formulation conditions were optimized from the drug release study. In vivo pharmacokinetics of the zinc-pectinate particles was compared with the zinc-pectin-chitosan composite particles in rats. Formulations were spherical with 920.48-1107.56 μm size, 21.19-24.27 mg weight of 50 particles, 89.83-94.34% WL, 8.31-13.25% MC, 96.95-98.85% EE, and 17.82-48.31% L. Formulation parameters showed significant influence on drug release pattern from the formulations. Formulation prepared at pH 1.5, 1% chitosan, 120 min cross-linking time, and pectin:drug at 3:1 ratio demonstrated colon-specific drug release. Microparticles were stable at 4 °C and room temperature. Pharmacokinetic study indicated in vivo colon-specific drug release from the zinc-pectin-chitosan composite particles only.

Lipid-Based Nanoparticulate Systems for the Delivery of Anti-Cancer Drug Cocktails: Implications on Pharmacokinetics and Drug Toxicities

The use of drug cocktails has become a widely adopted strategy in clinical cancer therapy. Cytotoxic drug cocktails are often administered based on maximum tolerated dose (MTD) of each agent, with the belief of achieving maximum cell kill through tolerable toxicity level. Yet, MTD administration may not have fully captured the therapeutic synergism that exists among the individual agents in the drug cocktail, as the response to a cocktail regimen, that is, whether the effect is synergistic or not, could be highly sensitive to the concentration ratios of the individual drugs at the site of action. It is important to realize that the inherently different pharmacokinetic profiles of the individual agents could have significant influence on the response to an anti-cancer drug cocktail by dictating the amount of the individual agents reaching the tumor site and therefore the concentration ratios. Furthermore, the individual agents may have unfavorable pharmacokinetic interactions that add to the difficulty in determining the therapeutic and/or toxicological effects of the drug cocktail. In this review, we will focus on how lipid-based nanoparticulate systems could address the above issues associated with anti-cancer drug cocktails. Specifically, we will highlight the use of liposome systems as the means to control and coordinate the delivery of various anti-cancer drug cocktails, encompassing conventional chemotherapeutics, chemosensitizing agents and molecularly targeted agents.

Liposome co-encapsulation of synergistic combination of irinotecan and doxorubicin for the treatment of intraperitoneally grown ovarian tumor xenograft.

Liposome co-encapsulation of synergistic anti-cancer drug combination is an emerging area that has demonstrated therapeutic benefit in clinical trials. Remote loading of two or more drugs into a single liposome constitutes a new challenge that calls for a re-examination of drug loading strategies to allow the loading of the drug combination efficiently and with high drug content. In this study, the Mn2+ gradient coupled with A23187 ionophore was applied in the sequential co-encapsulation of doxorubicin and irinotecan, as this drug loading method is capable of remotely loading drugs by apparently two different mechanisms, namely, coordination complexation and pH gradient. Doxorubicin and irinotecan could be co-encapsulated into liposomes in a wide range of drug-to-drug ratio, with encapsulation efficiencies of >80%. The total encapsulated drug content was non-linearly correlated with increases in the intraliposomal Mn2+ concentration, with a maximum total drug-to-lipid molar ratio of 0.8:1 achieved with 600mM Mn2+. This high encapsulated drug content did not affect the stability of the co-encapsulated liposomes upon storage for six months. Regardless of the encapsulated drug amount, the liposomes did not exhibit the fiber bundle precipitate morphology but rather an undefined structural organization in the aqueous core. The co-encapsulated liposome formulation was further tested in an intraperitoneally grown, human ovarian tumor xenograft model, and was shown to significantly improve the survival of the tumor-bearing animals. The improvement in therapeutic efficacy was possibly due to the increase in systemic drug exposure, with the maintenance of the synergistic molar drug ratio of 1:1 in circulation.

Potent therapeutic activity of folate receptor-targeted liposomal carboplatin in the localized treatment of intraperitoneally grown human ovarian tumor xenograft.

Intraperitoneal (IP) therapy with platinum (Pt)-based drugs has shown promising results clinically; however, high locoregional concentration of the drug could lead to adverse side effects. In this study, IP administration was coupled with a folate receptor-targeted (FRT) liposomal system, in an attempt to achieve intracellular delivery of the Pt-based drug carboplatin in order to increase therapeutic efficacy and to minimize toxicity. In vitro and in vivo activity of FRT carboplatin liposomes was compared with the activity of free drug and nontargeted (NT) carboplatin liposomes using FR-overexpressing IGROV-1 ovarian cancer cells as the model. Significant reduction in cell viability was observed with FRT liposomes, which, compared with the free drug, provided an approximately twofold increase in carboplatin potency. The increase in drug potency was correlated with significantly higher cellular accumulation of Pt resulting from FRT liposomal delivery. Further evaluation was conducted in mice bearing intraperitoneally inoculated IGROV-1 ovarian tumor xenografts. A superior survival rate (five out of six animals) was achieved in animals treated with FRT carboplatin liposomes, injected intraperitoneally with a dose of 15 mg/kg and following a schedule of twice-weekly administration for 3 weeks. In contrast, no survivors were observed in the free drug or NT carboplatin liposome groups. The presence of cancer cells in lung and liver tissues was observed in the saline, free carboplatin, and NT carboplatin liposome groups. However, there was no sign of cancer cells or drug-related toxicity detected in tissues from the animals treated with FRT carboplatin liposomes. The results of this study have demonstrated for the first time that the approach of coupling IP administration with FRT liposomal delivery could provide significantly improved therapeutic efficacy of carboplatin in the treatment of metastatic ovarian cancer.

Lyophilization of cholesterol-free PEGylated liposomes and its impact on drug loading by passive equilibration

The obstacles in translating liposome formulations into marketable products could be attributed to their physical instabilities upon long-term storage as aqueous dispersions. Lyophilization is the most commonly used technique to improve physical stability of liposomes. The development of stable, lyophilized liposomes is focused primarily on the cholesterol-containing liposomes or pure phosphatidylcholine-based liposomes, with minimal studies on cholesterol-free, pegylated (CF-PEG) liposomes which have emerged as an important class of liposome drug carriers. Hence, it is our interest to investigate the effect of lyophilization on CF-PEG liposomes, and specifically, on drug loading via the passive equilibration method. Three different sugar cryoprotectants were used at two different sugar-to-lipid molar ratios (S/L). Our results demonstrated that CF-PEG liposomes lyophilized with sucrose at S/L=5:1 yielded the best cryoprotective effect, as characterized by size, polydispersity indices, and microscopic examination upon liposome reconstitution. The lyophilized liposomes had low water content of 2.59 ± 0.18%. Of note, lyophilized CF-PEG liposomes exhibited two-fold increase in drug content when carboplatin was loaded via the passive equilibration method, and the in vitro drug release profile of these liposomes were not different from that of the non-lyophilized counterparts. Taken together, we envisioned that a stable, lyophilized empty CF-PEG liposome system could be coupled to hydrophilic drug loading via the passive equilibration method to produce a liposomal drug kit product.

Folate Receptor Targeted Liposomes Encapsulating Anti-Cancer Drugs

Among all available lipid based nanoparticulate systems, the success of liposomal drug delivery system is evident by the number of liposomal products available in the market or under advanced stages of preclinical and clinical trials. Liposome has the ability to deliver chemotherapeutic agents to the targeted tissues or even inside the cancerous cells by enhanced intracellular penetration or improved tumour targeting. In the last decade, folate receptor mediated tumour targeting has emerged as an attractive alternative method of active targeting of cancer cells through liposomes due to its numerous advantages over other targeting methods. Folate receptors, also known as folate binding proteins, allow the binding and internalization of folate or folic acid into the cells by a method called folate receptor mediated endocytosis. They have restricted presence in normal cells and are mostly expressed during malignant transformation. In this review article, folate receptor targeting capability of liposomes has been described. This review article has focussed on the different cancer drugs which have been encapsulated in folate receptor targeted liposomes and their in vitro as well as in vivo efficacies in several tumour models.

Polyethyleneimine-modified pectin beads for colon-specific drug delivery: In vitro and in vivo implications

Calcium-pectinate (Ca-pectinate) beads have shown immense potential as colon-specific drug carrier. However, Ca-pectinate itself is unable to prevent its swelling/degradation in the upper gastro-intestinal (GI) conditions. Hence, polyethyleneimine (PEI) was added in the cross-linking solution to strengthen the Ca-pectinate network. Resveratrol was used as a model drug due to its promising therapeutic activity towards several colonic diseases. Beads were prepared by varying cross-linking solution pH and other formulation variables. The effects of these formulation variables were investigated on the beads characteristics. Furthermore, surface morphology, drug–polymer interaction, stability, and in vivo pharmacokinetic study of the optimized formulation were performed. The optimized PEI-modified beads prevented drug release in the upper GI conditions, while released the drug in simulated colonic fluid. Furthermore, in vivo pharmacokinetics studies in rats demonstrated delayed appearance of drug in blood after oral administration. The optimized Ca-pectinate beads demonstrated both in vitro and in vivo colon-specific drug release.

Potentials of polymeric nanoparticle as drug carrier for cancer therapy: with a special reference to pharmacokinetic parameters.

Nanomaterials have made a significant impact on cancer therapeutics and an emergence of polymeric nanoparticle provides a unique platform for delivery of drug molecules of diverse nature. Nanoparticles can be targeted at the tumor cells due to enhanced permeability and retention effect. Moreover, nanoparticles can be grafted by various ligands on their surface to target the specific receptors overexpressed by cancer cells or angiogenic endothelial cells. These approaches ultimately result in longer circulation half-lives, improved drug pharmacokinetics, reduced side effects of therapeutically active substances and overcoming cancer chemo-resistance thereby enhancing the therapeutic efficacy of the treatment. This review article summarizes the recent efforts in cancer nanochemotherapeutics using polymeric nanoparticles with a special reference to their pharmacokinetic and biodistribution profiles, their role in reversing multidrug resistance in cancer and strategies of tumor targeting with them, along with the challenges in the field.