Drug targeting to cancer by nanoparticles surface functionalized with special biomolecules

Nanoparticulate-based drug carriers have been developed to overcome the problems of conventional anticancer pharmacotherapy, i.e., the little specificity and low accumulation of the drug into the tumor interstitium, and the extensive biodistribution leading to severe toxicity. Unfortunately, conventional nanoparticles have been demonstrated to merely accumulate the loaded drug into organs associated to the reticuloendothelial system, e.g., the liver. Recently, drug delivery strategies involving the use of nanoplatforms surface decorated with unique biomolecules have demonstrated their potential in concentrating the chemotherapy agent specifically into the malignant cells. This review will be focused on the analysis of the current state of the art and future perspectives of such passive and active targeting strategies based on the enhanced permeability and retention effect and on a ligand-mediated transport, respectively. Special attention will be given to the use of these surface functionalized nanocarriers to overcome multi-drug resistances in cancer cells.     

Drug delivery to inflammation based on nanoparticles surface decorated with biomolecules

Anti-inflammatory molecules often display little affinity for inflamed tissues, leading to low accumulation into this site of action (and inefficiency), and high incidence of severe side effects. To face the problem, numerous strategies have been proposed, i.e., chemical modifications to the drug molecule, and engineering of drug nanocarriers. The later approach to the problem can result in optimized drug biodistribution and concentration into the target region, thus enhancing the anti-inflammatory effect while reducing the associated drug toxicity. Such nanoparticulate systems offer remarkable possibilities when they are made of biodegradable polymers, lipid-based structures, and/or inorganic particles. Recent advances in the field have been devoted to the optimization of the in vivo fate and effectiveness of these drug nanocarriers, e.g., passive targeting strategies based on the functionalization of nanoparticle surface with special biomolecules. In this contribution, we analyze the possibilities and future perspectives of nanoparticle therapy in inflammatory processes.     

Active drug targeting of disease by nanoparticles functionalized with ligand to folate receptor

Drug-loaded nanoparticles have shown great potential in the study of carriers for disease-targeting drug delivery. Drug-loaded nanoparticles are excellent in keeping the drug in the systemic circulation for a prolonged period of time, introducing targeting molecules to improve targeting efficiency and to reduce side effects. A general review on active drug targeting of cancerous diseases by nanoparticles functionalized with ligands to folate receptors is presented including the (1) materials and methods for nanoparticle preparation, (2) methods for drug encapsulation, (3) surface functionalization of the nanoparticle with ligand to folate receptors, and (4) in vitro and in vivo experiments.     

Drug targeting by surface cationization

Cationization of drug products and carriers involves a direct modification or attachment of conveying or accompanying components, either of which cause a charge modification. Cationization of macromolecules such as proteins and nucleotides and particulate drug carriers generally enhances their cellular uptake by endocytosis. The most common use of cationization today is in gene delivery. This is undertaken by either employing cationic polymers or entraping nucleotides in cationic carriers such as cationic liposomes. Cationized delivery systems are also used to overcome biological barriers and are suggested for drug targeting, in a nonspecific manner, to a variety of body organs, including brain, eyes, nose, and inflamed intestinal epithelium. Protein cationization is also suggested both for tumor immunotherapy and as a diagnostic tool in cancer therapy. Cationization has proven itself to be a straightforward tool for targeting to cells, tissues, and selected organs. This article reviews the extensive range of applications of cationization for improving drug and gene delivery and summarizes major technologies employed for that purpose.     

Drug delivery system to control infectious diseases

Viral replication takes place only in the host cell. From this intrinsic characteristics of virus, therapeutics agents specifically target to the virus genome is quite difficult. However, genetic medicine toward viral gene is promising in terms of selective toxicity for viral infection. Genetic medicine including antisense DNA, ribozyme, aptamer, triplex and gene itself has been enthusiastically studied in the past decades. At the early age of genetic medicine research, there were many skepticisms about clinicla usage. However, the first antisense DNA is on the market in the USA and Europe. Although the mechanism of antisense manner is still controversial, it was clearly epoch-making in the human application of genetic medicine. Genetic medicine opens the possibility to combat virus replication in a sequence specific way. Virus utilizes the specific receptor on the host cells for entry; this is the reason why virus has organ specificity (tropism). Since life cycle of each virus is unveiled, target for the therapeutic agent's reveals in a molecular level. Furthermore, decipher of viral genome has been carried out rapidly and inexpensively. Once we hand entire sequences of viral genome, more theoretical way to design genetic medicine targeted viral infection could be main stream in the development of antiviral agents. Furthermore, efficient drug delivery system (DDS) to deliver antiviral agents to the infectious site is highly needed. In this article, we will address the target molecule of antiviral agents and possible DDS for the infectious disease.     

Drug targeting by solid lipid nanoparticles for dermal use

Long term topical glucocorticoid treatment can induce skin atrophy by the inhibition of fibroblasts. We, therefore, looked for the newly developed drug carriers that may contribute to a reduction of this risk by an epidermal targeting. Prednicarbate (PC, 0.25%) was incorporated into solid lipid nanoparticles of various compositions. Conventional PC cream of 0.25% and ointment served for reference. Local tolerability as well as drug penetration and metabolism were studied in excised human skin and reconstructed epidermis. With the latter drug recovery from the acceptor medium was about 2% of the applied amount following PC cream and ointment but 6.65% following nanoparticle dispersion. Most interestingly, PC incorporation into nanoparticles appeared to induce a localizing effect in the epidermal layer which was pronounced at 6 h and declined later. Dilution of the PC-loaded nanoparticle preparation with cream (1:9) did not reduce the targeting effect while adding drug-free nanoparticles to PC cream did not induce PC targeting. Therefore, the targeting effect is closely related to the PC-nanoparticles and not a result of either the specific lipid or PC adsorbance to the surface of the formerly drug free nanoparticles. Lipid nanoparticle-induced epidermal targeting may increase the benefit/risk ratio of topical therapy.     

Self-assembly and liver targeting of sulfated chitosan nanoparticles functionalized with glycyrrhetinic acid

A drug carrier based on glycyrrhetinic acid-modified sulfated chitosan (GA-SCTS) was synthesized. The glycyrrhetinic acid (GA) acted as both a hydrophobic group and a liver-targeting ligand. The GA-SCTS micelles displayed rapid and significant ability to target the liver in vivo. The IC(50) for doxorubicin (DOX)-loaded GA-SCTS micelles (DOX/SA-SCTS micelles) against HepG2 cells was 54.7 ng/mL, which was extremely lower than the amount of no-GA-modified DOX-loaded micelles. In addition, DOX/SA-SCTS micelles could target specifically the liver cancer cells. They had higher affinity for the liver cancer cells (HepG2 cells) than for the normal liver cells (Chang liver cells). There was nearly 2.18-fold improvement in uptake of the DOX/SA-SCTS micelles by HepG2 cells than that by Chang liver cells. These results indicate that GA-SCTS is not only an excellent carrier for drugs, but also a potential vehicle for liver-cancer targeting.     

Nuclear penetration of surface functionalized gold nanoparticles

Free gold nanoparticles easily aggregate when the environment conditions change. Here, gold nanoparticles (AuNPs) with average diameter of 3.7 nm were prepared and then modified with poly(ethylene glycol) (PEG) to improve stability. The gold nanoparticles were first surface-modified with 3-mercaptopropionic acid (MPA) to form a self-assembled monolayer and subsequently conjugated with NH₂-PEG-NH₂ through amidation between the amine end groups on PEG and the carboxylic acid groups on the particles. The biocompatibility and intracellular fate of PEG-modified gold nanoparticles (AuNP@MPA-PEG) were then studied in human cervical cancer (HeLa) cells. Cell viability test showed that AuNP@MPA-PEG did not induce obvious cytotoxicity. Both confocal laser scanning microscopy and transmission electron microscopy demonstrated that AuNP@MPA-PEG entered into mammalian cells and the cellular uptake of AuNP@MPA-PEG was time-dependent. Inductively coupled plasma mass spectrometry and confocal microscopy imaging further demonstrated that AuNP@MPA-PEG penetrated into the nucleus of mammalian cells upon exposure for 24 h. These results suggest that surface modification can enhance the stability and improve the biocompatibility. This study also indicates that AuNP@MPA-PEG can be used as potential nuclear targeted drug delivery carrier.     

Nose-to-brain delivery of temozolomide-loaded PLGA nanoparticles functionalized with anti-EPHA3 for glioblastoma targeting

Glioblastoma is the most common malignant brain tumor. Efficient delivery of drugs targeting glioblastomas remains a challenge. Ephrin type-A receptor 3 (EPHA3) tyrosine kinase antibody-modified polylactide-co-glycolide (PLGA) nanoparticles (NPs) were developed to target glioblastoma via nose-to-brain delivery. Anti-EPHA3-modified, TBE-loaded NPs were prepared using an emulsion-solvent evaporation method, showed a sustained in vitro release profile up to 48 h and a mean particle size of 145.9 ± 8.7 nm. The cellular uptake of anti-EPHA3-modified NPs by C6 cells was significantly enhanced compared to that of nontargeting NPs (p < .01). In vivo imaging and distribution studies on the glioma-bearing rats showed that anti-EPHA3-modified NPs exhibited high fluorescence intensity in the brain and effectively accumulated to glioma tissues, indicating the targeting effect of anti-EPHA3. Glioma-bearing rats treated with anti-EPHA3-modified NPs resulted in significantly higher tumor cell apoptosis (p < .01) than that observed with other formulations and prolonged the median survival time of glioma-bearing rats to 26 days, which was 1.37-fold longer than that of PLGA NPs. The above results indicated that anti-EPHA3-modified NPs may potentially serve as a nose-to-brain drug carrier for the treatment of glioblastoma.     

Multifunctional nanoparticles for targeting cancer and inflammatory diseases

Abstract

The interplay between cancer and inflammation has been well documented over the years and the role of nanomedical technologies for treating both these diseases has become evident over the past few decades. With the advances in nanoparticle-based imaging and therapeutic platforms that can exploit the pathological conditions of the tumor and the inflamed sites to effectively deliver drugs, genes and imaging/contrast agents; the management of such conditions with favorable therapeutic outcomes seems plausible. This review will summarize some of the latest advances in the field of targeted nanomedicine development to combat cancer and inflammation. Illustrative examples of multifunctional-targeted nanosystems are presented that highlight their potential in delivering diverse payloads, including small molecule drugs, nucleic acids and imaging agents for simultaneous theranostic interventions.     

CpG oligonucleotides as adjuvants for vaccines targeting infectious diseases

Synthetic oligodeoxynucleotides (ODN) containing unmethylated CpG motifs act as immune adjuvants, accelerating and boosting antigen-specific immune responses. CpG motifs promote the induction of Th1 and pro-inflammatory cytokines and support the maturation/activation of professional antigen presenting cells (particularly plasmacytoid dendritic cells). These effects are optimized by maintaining close physical contact between the CpG ODN and the immunogen. Co-administering CpG ODN with a variety of vaccines has improved the resultant humoral and/or cellular immune responses, culminating in enhanced protective immunity in rodent and primate challenge models. Ongoing clinical studies indicate that CpG ODN are safe and well-tolerated when administered as adjuvants to humans, and that they can support increased vaccine-specific immune responses.     

Drug targeting to lungs by way of microspheres

In many conventional drug delivery systems in vogue, failure to deliver efficient drug delivery at the target site/organs; is evident as a result, less efficacious pharmacological response is elicited. Microspheres can be derived a remedial measure which can improve site-specific drug delivery to a considerable extent. As an application, Lung-targeting Ofloxacin-loaded gelatin microspheres (GLOME) were prepared by water in oil emulsion method. The Central Composite Design (CCD) was used to optimize the process of preparation, the appearance and size distribution were examined by scanning electron microscopy, the aspects such as in vitro release characteristics, stability, drug loading, loading efficiency, pharmacokinetics and tissue distribution in albino mice were studied. The experimental results showed that the microspheres in the range of 0.32-22 microm. The drug loading and loading efficiency were 61.05 and 91.55% respectively. The in vitro release profile of the microspheres matched the korsmeyer's peppas release pattern, and release at 1h was 42%, while for the original drug, ofloxacin under the same conditions 90.02% released in the first half an hour. After i.v. administration (15 min), the drug concentration of microspheres group in lung in albino mice was 1048 microg/g, while that of controlled group was 6.77 microg/g. GLOME found to release the drug to a maximum extent in the target tissue, lungs.     

Therapeutic targeting of Toll-like receptors for inflammatory and infectious diseases

Roles for Toll-like receptors (TLRs) are emerging in conditions such as sepsis syndrome, systemic lupus erythromatosis, rheumatoid arthritis and asthma, suggesting that the selective targeting of TLRs might be useful therapeutically. TLRs are defined by the presence of extracellular leucine-rich repeats and an intracellular Toll/interleukin-1 receptor domain, and play a role in host defence and inflammation. Signalling pathways activated by TLRs show remarkable similarity to those activated by the pro-inflammatory cytokine interleukin-1 (the receptor for which also has a Toll/interleukin-1 receptor domain), although adaptor proteins specific for certain TLRs are starting to emerge (e.g. Mal and Trif). The common signalling pathways used by all members of the TLR superfamily are being targeted, with drugs that block nuclear factor-kappaB and p38 mitogen-activated protein kinase in clinical development for diseases such as rheumatoid arthritis and psoriasis. As we learn more about TLR signal transduction, more options are presenting themselves for pharmacological targeting.     

Drug targeting to inflammation: studies on antioxidant surface loaded diclofenac liposomes

Inflammation is associated with enhanced vascular permeability, production of inflammatory markers and over production of reactive oxygen species (ROS) with depletion of endogenous antioxidants. Several drug targeting approaches to inflammation taking clues from these events have been evolved. Surprisingly, a drug targeting approach utilizing abundant oxidative stress at inflammatory site has not been followed. Antioxidant surface loaded liposomes might preferentially localize at inflammatory sites via redox interaction where at high level of ROS exist. The present study was focused to investigate the role of antioxidant as a targeting ligand on the surface of liposome employing rat granuloma air pouch model of inflammation. We developed conventional and antioxidant loaded diclofenac (DFS) liposomes (co-enzyme Q10 and ascorbyl palmitate) for i.v. administration and characterized for vesicle size, zeta potential and percent entrapment. In vivo drug targeting studies showed an increase in AUC, therapeutic availability of DFS in air pouch fluid (APF) and APF/serum DFS concentration ratios from antioxidant loaded liposomes compared to conventional liposomes and drug solution. The promising results suggest the role of antioxidant as a possible ligand in drug targeting to a site where at abundant ROS exist.     

Drug delivery to the brain with nanoparticles

Drugs can be delivered to brain with the aid of poly(butylcyanoacrylate) (PBCA) nanoparticles coated with polysorbate 80. These carriers can penetrate BBB and deliver drugs of various structures, including peptides, hydrophilic compounds, and lipophilic compounds eliminated from brain with P-glycoprotein. When a suspension of polysorbate-coated PBCA nanoparticles is introduced into blood, apolipoproteins of the blood plasma adsorb on the particle surface and then interact with receptors of low-density lipoproteins situated in endothelial cells of cerebral vessels, thus stimulating endocytosis.     

Chitosan nanoparticles in drug therapy of infectious and inflammatory diseases

ABSTRACT

Introduction: Chitosan, a polymer from the chitin family has diverse pharmaceutical and bio-medical utility because of its easy widespread availability, non-toxicity, biocompatibility, biodegradability, rich functionalities and high drug-loading capacity. Recent pharmaceutical research has examined the use of chitosan-based systems for drug delivery applications in various diseases. The availability of functional groups permits the conjugation of specific ligands and thus helps to target loaded drugs to the site of infection/inflammation. Slow biodegradation of chitosan permits controlled and sustained release of loaded moieties; reduces the dosing frequency and is useful for improving patient compliance in infectious drug therapy. The muco-adhesion offered by chitosan makes it an attractive candidate for anti-inflammatory drug delivery, where rapid clearance of the active moiety due to the increased tissue permeability is the major problem. The pH-dependent swelling and drug release properties of chitosan present a means of passive targeting of active drug moieties to inflammatory sites.

Areas covered: Development of chitosan-based nanoparticulate systems for drug delivery applications is reviewed. The current state of chitosan-based nanosystems; with particular emphasis on drug therapy in inflammatory and infectious diseases is also covered.

Expert opinion: The authors believe that chitosan-based nanosystems, due to the special and specific advantages, will have a promising role in the management of infectious and inflammatory diseases.