Polymeric Nanomedicines

The chapter deals with the definition of nanotechnology and nanomedicine, with main area of applications and specifies the benefits of introducing nanotechnological specific methods in the investigation and treatment of certain diseases. The main categories of metal nanoparticles, their use as imaging agents, their advantages and limits are presented in separate paragraphs. Finally, toxicological aspects are discussed.

This chapter describes the concept of physical and biological targeting. Physical targeting consists of a series of physical techniques to enhance drug delivery, such as electroporation, magnetofection, ultrasound, photochemical internalization, and hypothermia. Biological targeting strategies can be divided in passive and active targeting.Passive targeting refers to the exploitation of the natural (passive) distribution pattern of a drug carrier in vivo. This phenomenon is based upon the process named “enhanced permeability and retention (EPR)” effect. The active approach relies upon the selective localization of a ligand at a cell-specific receptor. In this chapter we describe the advantages of macromolecular support in the design of drug delivery systems and various applications of active pargeting especially in the treatment of cancer.

On 17 January 2007, the European Group of Ethics (EGE) issued a draft report that recognized the potential of nanomedicine in terms of developing new diagnostics and therapies (http://ec.europa.eu/european _group_ethics/activities /ethics_en.htm). The group proposes that measures be established to verify the safety of nanomedical products and devices, and calls on the relevant authorities to carry out a proper assessment of the risks and safety of nanomedicine. This chapter deals with toxicological aspects of various nanoparticles such as polymer-drug conjugates, carbon nanotubes, quantum dots, dendrimers and other various nanostructures. The nanoparticle-biological organism interactions and immunological risk of the nanoparticles are also examined in this chapter.

This chapter summarizes the exploitation of drug loaded nanocarrier conjugates with various targeting moieties for the delivery and targeting of drugs and describes the current status of and challenges in the field of nanocarrier-aided drug delivery and drug targeting. The discovery of targeting ligands and the development of ligand targeted therapy will help us to improve therapeutic efficacy and reduce side effects. Unlike other forms of therapy, it will allow us to maintain quality of life for patients, while efficiently attacking diseased cells and indicates that ligands have a pivotal role especially in cancer cell targeting.

In this chapter we describe a series of polymer-drug conjugates synthesized in the last years. Our attention have been focused on known macromolecular supports such as poly(ethylene glycol) and N-(2-hydroxypropyl)methacrylamide (HPMA) copolymers, as well as the novel macromolecular supports recently used in the synthesis of polymer-drug conjugates poly(amino acid)s, polylactides, cyclodextrins, poly(β,L-malic acid), hyaluronan, and chitosan. This chapter also describes the novel strategies such as combination chemotherapy, photodynamic therapy (PDT) and polymer-directed enzyme prodrug therapy (PDEPT) are included.

This chapter provides a brief description of the synthesis, biological evaluation, and biomedical applications of dendrimers especially in dendrimer-mediated cancer therapy in the last decade with an emphasis on the development and use of dendrimers in cancer therapeutics.

In this chapter, polymeric micelle drug carrier systems are discussed with a focus on synthesis and characterization of micellar drug delivery systems. The design, types and classifications of the polymeric micelle systems are summarized and explained, followed by a detailed discussion regarding several examples of polymeric micelle carrier systems that were tested in clinical trials. The toxicity and pharmacological activity of these systems are also discussed.

Cancer represents one of the world’s most devastating diseases. Current cancer treatments include surgical intervention, radiation and chemotherapeutic drugs, which often also kill healthy cells and cause toxicity to the patients. Tumor specific drug delivery has become increasingly interesting in cancer therapy, as the use of chemotherapeutics is often limited due to severe side effects. Conventional drug delivery systems have shown low efficiency and a continuous search for more advanced drug delivery principles is therefore of great importance. Liposomes as pharmaceutical drug carriers were developed to increase antitumour efficacy and decrease drug toxicity. As a biodegradable and essentially nontoxic platform, liposomes can be used to encapsulate both hydrophilic and hydrophobic active principles and be utilised as drug carriers in drug delivery systems. The objective of this chapter is to discuss some clinical application of liposomes as drug delivery systems in the treatment of carcinomas (cancers of the epithelial cells).

Polymersomes represent the latest generation of colloidal vesicles for drug carriers. As well as liposomes, they can include hydrophilic molecules in their interior core and also hydrophobic molecules in their surrounding polymeric membrane. The vesicular nature of these particles, for which the free volume represent over 90% of their global volume, makes it possible to include large amounts of drugs and of course, their transportation to the target. This chapter present the methods used for obtaining and characterizing polymersomes and also their applications as drug carriers or as diagnostic tools.

The brain is the most complex and remarkable organ in the human body because it is responsible for memories, movement, feelings, intelligence, emotions and desires determining the uniqueness of each person. This organ is protected against various harmful substances due to the presence of two types of barriers: the blood-brain barrier and the blood cerebrospinal fluid barrier. The blood-brain barrier is an important limiting factor for the development of new drugs that can be delivered to the central nervous system. For this reason different approaches have been developed in order to overcome this barrier. Polymeric nanoparticles represent one of the most stimulating challenges for the scientific world, being investigated as drug delivery systems for effective systemic and local delivery of therapeutics to the central nervous system. This chapter presents in introduction a classification of the central nervous diseases followed by a presentation of different strategies that have been developed in order to obtain the polymeric nanoparticles as well as their applications for treatment and prevention of some central nervous diseases.

Polymer nanocapsules are widely used in the biomedical field, especially as carriers for controlled drug delivery. The main preparation methods are described in the paper (nanoprecipitation, emulsion-diffusion, double emulsification, emulsion-coacervation, polymer-coating, layer-by-layer and interfacial polycondensation), emphasizing the role of different parameters on drug encapsulation efficiency and drug release profiles. Mechanisms of drug loading and releasing are also shortly discussed. The paper ends with the presentation of the major biomedical applications (drug delivery and diagnosis) of polymer nanocapsules, the discussion being directed toward several routes of drug administration.

Bladder cancer is the ninth most common malignancy in the world featuring very high gender variability in occurrence. Current options for bladder cancer therapy include surgery, immunotherapy and radiotherapy with a trend towards multimodal treatments. However, successful management remains a challenge for urologists and oncologists because of the high risk for recurrence and progression. Particularly in the field of bladder cancer chemotherapy, efficacy of treatment might be improved by advanced drug delivery strategies aimed at prolonged residence time within the bladder cavity and increased permeability of the bladder-wall during intravesical instillation. Thus, encapsulation of the drug in various nanosystems, photodynamic therapy, mucoadhesion and targeted durgs are several strategies used in the treatment of bladder cancer. Moreover, a deeper understanding of the biology of bladder carcinogenesis and malignant progression stimulated the development of a new generation of anticancer drugs for targeted therapies that might result in increased specificity together with lower toxic potential and higher therapeutic indices. In addition, this chapter discusses the available strategies for “targeted therapies”, focusing on molecular targets and the role of polymeric nanoparticles in the development of targeted therapy of bladder cancer.

A new dawn in the treatment for kidney patients prefigures in the same time with the raised challenges by novel discovered polymeric systems. Since a very large number of present diseases have the main generating mechanism at nanoscale levels, nanomedicine could bring huge improvements in their treatment or early diagnosis. Nanonephrology, which is an extension of nanomedicine, besides an investigation of kidney processes on cellular levels, is mainly focused on the management of kidney patients with outcome innovating nanomedical therapies. Renal diseases, an expanding world’s health priority, benefit in the present days only from classical treatments as dialysis and kidney transplantation that are considered to be life-saving alternatives with the main disadvantage in the same time represented by high costs supported by national health funds. Acute kidney injuries and chronic kidney diseases, the major renal disorder categories, could take future advantages on novel polymeric systems improved and adapted in order to achieve kidney targeting in an active and close manner. From organ regeneration to functional imaging, polymers as PEG, PVD, PLGA, polysaccharides as chitosan with various modifications or PAMAM dendrimers may successfully be used in alternative therapies for renal diseases. In this chapter the main applications of these polymers as nanomedicines are detailed.

The development of formulations with modified release of the drug substances targeting different segments of the gastrointestinal tract is an ongoing challenge for the scientist in the field of drugs. Current manufacturing technologies are mainly focused on delayed release so that the release does not start before the formulation reaches the colon. Other technologies are based on time-delayed active substance release with a predetermined lag time, on time-delayed controlled release systems with enzymes, and on pressure controlled release systems. The release of medicinal substances incorporated into colonic-release microparticulate systems is dependent on pH, on the system's gastrointestinal transit time or on the microbial and enzymatic load of the colon. Colonic release micro/nanoparticulate systems based on natural polymers led to significant results. Recent research has shown that the most effective colon-specific micro/nanoparticulate systems are those combining several drug release principles.

This chapter presents literature data on the studies focused on nanoparticulate systems and on pulmonary drugs delivery as a non-invasive alternative for the controlled release of therapeutic agents both in systemic and local treatments. The large lung surface and the existence of minimal barriers that prevent access to pulmonary peripheral make this organ a suitable portal for various therapeutic strategies. The nanotransporters employed in the pulmonary drug delivery provide several advantages, such as the relatively smooth distribution of the drug dose in the alveoli, a better drug solubilisation and the controlled drug release which reduces the administration frequency and decreases the incidence of side-effects. Both the methods of obtaining nanoparticles suitable for improving access to lung peripheral areas and the in vitro/in vivo assessment methods and the toxicity studies have been analyzed.

Inflammation is a complex neurotropic, vascular and metabolic reaction, triggered by the pervasion of the healthy tissues of the body by pathogenic vascular agents, either external or produced by internal degradation. In this chapter are presented nanomedicines with anti-inflammatory substances active in the treatment of the major inflammatory diseases: ocular diseases (uveitis), bowel diseases, rheumatoid arthritis and multiple sclerosis. The efforts of researchers in recent decades have resulted in numerous innovations in nanomedical systems that improve targeted substance release. Many of these nanoparticulate systems have significant potential for clinical applications. New inflammatory nonsteroidal substances were discovered and new ways have been proposed for active substances targeted release: polymeric and lipidic nanoparticles, liposomes, microemulsions, monocrystals of medicinal substances, polymer-drug conjugates, polymeric micelles, polymersomes, dendrimers etc.

It is well known that the eye is one of the most complex organs of the human body. The anatomy, physiology, and biochemistry of the eye render this organ highly impervious to foreign substances. A permanent challenge for the scientific world is to develop formulations able to circumvent the protective barriers of the eye without causing any permanent tissue damage. For drug delivery at ocular level, the physiological barriers imposed by the protective mechanisms of the eye generally lead to poor absorption of drugs, many times small fractions of the administered dose penetrate the cornea reaching the intraocular tissues. This is the reason for which there is a continuous concern on the development of more sensitive diagnostic techniques and novel therapeutic formulations with higher and higher therapeutic efficacy and with a better compliance for the patient. One of the major objectives of clinical therapeutics is to ensure and maintain an adequate concentration of drugs at the site of action. Lately, it seems that the researchers’ attention is focused on the different types of nanocarriers: polymeric nanoparticles, liposomes, metallic or ceramic nanoparticles, dendrimers, niosomes, etc, each of them with properties which make them suitable for a specific application. In this chapter, the applications of nanosystems in controlled drug delivery, in gene therapy, ocular tissue replacement and “smart” applications in eye pathology are detailed. Recent studies of researchers from different laboratories are brought together to underline the complexity and the importance of the nanoophthalmology for the human health.

Transdermal drug delivery has not yet reached its full potential as medical practice in order to successfully replace the classical routes for systemic drug delivery like oral ingestion or hypodermic injections. However, significant and promising progress has been registered in the past decades. Novel medical devices which are acting at nanometer level to ensure suitable drug delivery in compliance with the latest medical regulations appear on the medical market and transdermal drug delivery (TDD) systems make no exception. The present work reviews some of the most important achievements in the field of nano-designed materials with application in transdermal drug delivery. First, the specific problems encountered in drug transportation across skin barrier are shortly addressed. Particulate systems used for TDD like liposomes or polymeric nanoparticles receive a special attention. The involvement of polymer enhancers and cyclodextrins in TDD is also reviewed.

This chapter deals with the development and progression of metallic stents, as well as with the research and clinical trials of the bioabsorbable stents. Despite of the good results obtained with the metallic stents, many concerns still remain because of their permanent nature. Although metallic stents are effective in preventing recoil and late restenosis after coronary angioplasty, they continue to have limitations such as stent thrombosis and mismatch of the stent to the vessel size. Thus, the concept of bioabsorbable stents has emerged as an alternative to permanent metal stent. This chapter will outline concepts, material designs, preclinical, and metal clinical experimental studies with bioabsorbable stents.

This chapter discusses recent studies that have been conducted to determine the implementation of nanomaterials as bone implants. In addition, this chapter comprises the applications of nanomaterials such as nanoparticles, nanofibers, nanotubes, nanocoatings and nanocomposites in bone and tissue repair. The results of recetly obtained clinical trials regarding the applications of new nanomaterials are also described in this chapter.

Currently, much of the work of nanotechnology in orthopedic surgery takes place in the laboratory setting or in early in vivo testing. Significant basic interdisciplinary research is needed to realize its full clinical potential. In addition, the biological, manufacturing, economic, and regulatory issues with respect to nanotechnology need to be addressed moving forward. Critical to the successful implementation of nanotechnology in orthopedics will be a multidisciplinary effort between industry and medicine.

This chapter describes the evolution of polymer chemistry in the last decades. Orientation towards chemistry of life, getting some macromolecular compounds with curative properties and involvement in nanobiotechnology were the main decisions that preserve the importance of this field. On the other hand, weak points of the polymers have been identified which often represent a barrier to full acceptance of polymers in medical practice.

Overcoming these barriers and integrating polymers in medical practice is conditioned by adopting an interdisciplinary atittude, by abandonment of low-performing methodology and by opening toward innovation and originality.