Multifunctional Systems for Combined Delivery, Biosensing and Diagnostics

354 Pages·2017·20.045 MB·English

by  Alexander Mihai Grumezescu (Eds.)

Multifunctional Systems
for Combined Delivery,
Biosensing and Diagnostics
Edited by
Alexandru Mihai Grumezescu
University Politehnica of Bucharest,
Bucharest, Romania
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Contributors
Albert Abhishek, Madurai Kamaraj University, Madurai, Aysen Gumustas, Ankara University, Ankara, Turkey
Tamil Nadu, India Mehmet Gumustas, Ankara University, Ankara;
Mohammad Firoz Alam, College of Pharmacy, Jazan Hitit University, Corum, Turkey
University, Jazan, Saudi Arabia P. Selcan Gungor-Ozkerim, Biomaterials Innovation
Neda Alasvand, Materials and Energy Research Center, Research Center, Brigham and Women’s Hospital;
Tehran, Iran Massachusetts Institute of Technology, Cambridge,
Maria H. Amaral, University of Porto, Porto, Portugal MA, United States
Ravindran Ankathil, Human Genome Centre, Health Abouelhag Hussien, College of Pharmacy, Jazan
Campus University Sains Malaysia, Kubang Kerian, University, Jazan, Saudi Arabia
Kelantan, Malaysia Farah Islam, College of Pharmacy, Jazan University,
Tarique Anwer, College of Pharmacy, Jazan University, Jazan, Saudi Arabia
Jazan, Saudi Arabia Aamena Jabeen, College of Pharmacy, Jazan University,
Uddhav S. Bagul, College of Pharmacy, Jazan University, Jazan, Saudi Arabia
Jazan, Saudi Arabia Ankit Jain, Dr. Hari Singh Gour Central University, Sagar,
Samrat Chakraborty, Jadavpur University, Kolkata, West Madhya Pradesh, India
Bengal, India Sanjay K. Jain, Dr. Hari Singh Gour Central University,
Walter F. da Silva Júnior, Federal University of Sagar, Madhya Pradesh, India
Rio Grande do Norte, UFRN, Natal, Rio Grande Gyas Khan, College of Pharmacy, Jazan University, Jazan,
do Norte, Brazil Saudi Arabia
Priscila da Costa Carvalho de Jesus, Center Joana Magalhães, UCIBIO/REQUIMTE, University
of Nanotechnology and Tissue Engineering, of Porto, Porto, Portugal
University of São Paulo (USP), Ribeirão Preto, Hamid Mahdavi, Iran Polymer and Petrochemical Institute,
São Paulo, Brazil Tehran; Islamic Azad University, Sarvestan Branch, Iran
Ádley A.N. de Lima, Federal University of Rio Grande do Sabyasachi Maiti, Gupta College of Technological
Norte, UFRN, Natal, Rio Grande do Norte, Brazil Sciences, Asansol, West Bengal, India
Jonas G. de Oliveira Pinheiro, Federal University of Hamid Mirzadeh, Amirkabir University of Technology,
Rio Grande do Norte, UFRN, Natal, Rio Grande Tehran, Iran
do Norte, Brazil Davod Mohebbi-Kalhori, University of Sistan and
Fabia J.J. de Souza, Federal University of Rio Grande do Baluchestan, Zahedan, Iran
Norte, UFRN, Natal, Rio Grande do Norte, Brazil Laboni Mondal, Jadavpur University, Kolkata, West
Moumita Dhara, Jadavpur University, Kolkata, West Bengal, India
Bengal, India Carlos D.L.F.A. Moreira, Federal University of
Lopamudra Dutta, Jadavpur University, Kolkata, West Rio Grande do Norte, UFRN, Natal, Rio Grande
Bengal, India do Norte, Brazil
Mohamed E. Elmobark, College of Pharmacy, Jazan Masoud Mozafari, Cellular and Molecular Research
University, Jazan, Saudi Arabia Center, Iran University of Medical Sciences,
Mohamadreza Baghaban Eslaminejad, Royan Institute Tehran, Iran
for Stem Cell Biology and Technology, ACECR, Biswajit Mukherjee, Jadavpur University, Kolkata, West
Tehran, Iran Bengal, India
Marilene Estanqueiro, University of Porto, Porto, Vinod S. Nair, Kerala University of Health Sciences,
Portugal Thrissur, Kerala, India
Sivasamy Gomathi, Madurai Kamaraj University, Aneta Ostróżka-Cieślik, Medical University of Silesia,
Madurai, Tamil Nadu, India Katowice, Poland
xi
xii Contributors
Sibel A. Ozkan, Ankara University, Ankara, Turkey Beata Sarecka-Hujar, Medical University of Silesia,
Tritsida Panyosak, University of Phayao, Phayao, Katowice, Poland
Thailand Ponnusamy Sasikumar, Madurai Kamaraj University,
Eldho Paul, Madurai Kamaraj University, Madurai, Tamil Madurai, Tamil Nadu, India
Nadu, India Farshid Sefat, University of Bradford, Bradford,
Paramita Paul, Jadavpur University, Kolkata, West United Kingdom
Bengal, India Govindan Sadasivam Selvam, Madurai Kamaraj
Marina Pinheiro, UCIBIO/REQUIMTE, University of University, Madurai, Tamil Nadu, India
Porto, Porto, Portugal Ceyda T. Sengel-Turk, Ankara University,
Fernando L. Primo, São Paulo State University Ankara, Turkey
(UNESP), Araraquara, São Paulo, Brazil Soma Sengupta, Jadavpur University, Kolkata,
Ahmad Rabiee, Iran Polymer and Petrochemical Institute, West Bengal, India
Tehran, Iran Mohammad A. Shamekhi, Iran Polymer and
Maryam Rahmati, Materials and Energy Research Petrochemical Institute, Tehran; Islamic Azad
Center, Tehran, Iran University, Sarvestan Branch, Iran
Jayakumar Rajadas, Stanford University, Palo Alto, CA, Rahimullah Siddiqui, College of Pharmacy, Jazan
United States University, Jazan, Saudi Arabia
Anjana Ravindran, Kerala University of Health Sciences, Sivagurunathan Moni Sivakumar, College of Pharmacy,
Thrissur, Kerala, India Jazan University, Jazan, Saudi Arabia
Ranjana Ravindran, Kerala University of Health José M. Sousa Lobo, University of Porto,
Sciences, Thrissur, Kerala, India Porto, Portugal
Salette Reis, UCIBIO/REQUIMTE, University of Porto, Antonio C. Tedesco, Center of Nanotechnology and
Porto, Portugal Tissue Engineering, University of São Paulo (USP),
Chandrababu Rejeeth, Bharathiar University, Ribeirão Preto, São Paulo, Brazil
Coimbatore, Tamil Nadu, India; Shanghai Jiao Tong Ramar Thangam, Bharathiar University, Coimbatore;
University, Shanghai, China King Institute of Preventive Medicine and Research,
Natalya I. Rekoslavskaya, Siberian Institute of Plant Chennai, Tamil Nadu, India
Physiology and Biochemistry of SB RAS; Irkutsk Aleksandra M. Urbanska, Irving Cancer Research
Scientific Center (FASO), Irkutsk, Russia Center, Columbia University, New York, NY,
Maryam Saeidifar, Materials and Energy Research United States
Center, Tehran, Iran Bengi Uslu, Ankara University, Ankara, Turkey
Mohammed M. Safhi, College of Pharmacy, Jazan Alexandre Vieira, UCIBIO/REQUIMTE, University of
University, Jazan, Saudi Arabia Porto, Porto, Portugal
Rurik K. Salyaev, Siberian Institute of Plant Physiology Raju Vivek, Bharathiar University, Coimbatore, Tamil
and Biochemistry of SB RAS, Irkutsk, Russia Nadu, India; Shanghai Jiao Tong University, Shanghai,
Susana Santos, INEB—Institute of Biomedical China
Engineering, i3S-Institute of Research and Innovation Foziyah Zakir, College of Pharmacy, Jazan University,
in Health, University of Porto, Porto, Portugal Jazan, Saudi Arabia
Foreword
Despite the huge progress in medical-related areas, numerous diseases are still far from being efficiently detected, treated,
or prevented. The lack of success of current biomedical approaches relies on the complexity of some diseases, but also
on their very diverse clinical symptoms, and wide variations among patients. A failed or incorrect detection of a health-
threatening condition in its early stages usually leads to fatal effects on the patient. Moreover, wrong or late diagnosis
involves increased costs, prolonged hospital stays, and numerous other patient and socioeconomical-related issues. In this
context, a highly sensitive multifunctional system, able to detect, target and cure, or even prevent a health-damaging condi-
tion, is a widely investigated desiderate at the present time. Nanostructured sensors and drug-delivery systems bring a new
light in the research and management of serious diseases, by ensuring a specific effect, a very targeted and controllable
efficiency, and much lower side-effects, by being able to avoid damaging unaffected tissue.
This book brings an updated and clear picture regarding the recent progress made in the field of disease detection, but
also targeted nanodelivery of drugs for a wide variety of diseases, also aiming to offer a perspective for future approaches
in diagnosis, treatment, and prophylaxis.
A special attention is paid to the management of cancer, which is considered the disease of the century, and for whose
research and therapy a huge amount of resources is invested annually. In this particular field, the design and implementation
of multifunctional nanosystems represent the most feasible alternative for an efficient management, and it is considered a
real strategy for reducing mortality and morbidity.
The Editor selected the most recent, interesting, and innovative approaches, transposed in well-organized chapters, to
offer a scientifically, updated but, at the same time, very accessible material for a wide audience.
The book represents an attractive collection of up-to-date information in the field of multifunctional systems that can be
simultaneously utilized for the detection and therapy of diseases, and is an important source of knowledge, offering at the
same time novel perspectives in a very dynamic and challenging area.
Alina Maria Holban
University Politehnica of Bucharest, Bucharest, Romania
Monica Cartelle Gestal
University of Georgia, Athens, GA, United States
xiii
Preface
Numerous and varied diseases have emerged this century. In the context of constantly changing societies and population
requirements, the medical field requires faster and more versatile tools for improved diagnosis and therapy.
Multifunctional systems, designed at the micro- and nanoscale, were recently optimized not only to ensure a more ef-
ficient detection of diseases, but also a more personalized therapy.
Biosensing coupled with the delivery of active formulations may represent a great solution to numerous difficult-to-treat
and even incurable diseases. The use of very small devices to achieve a versatile diagnosis tool represents one of the most
investigated aspects in the field of biomedicine. Progress made in the field of material engineering offered researchers and
clinicians valuable alternatives in diagnosis, therapy, and prophylaxis, bringing at the same time a new light on the quality
of life and survival expectance in critical patients.
This book reviews and discusses the most novel and intriguing progress made in the field of multifunctional systems de-
veloped for diagnosis and therapy, with an emphasis on drug delivery and bioengineering progress in medical nanosystems.
The book contains 17 chapters, prepared by outstanding international researchers from the United States, Iran, Russia,
Saudi Arabia, Poland, India, Turkey, Portugal, Malaysia, Brazil, and Thailand.
Chapter 1, prepared by Tritsida Panyosak and entitled Selective effects of azelaic acid in nanovesicles on cell lines,
presents an up-to-date overview of an efficient therapeutic application for azelaic acid entrapped in bilayer vesicles for
cancer treatment.
Antonio Claudio Tedesco et al. in Chapter 2, entitled Antimicrobial photodynamic therapy (APDT) action based on
nanostructured photosensitizers, present novel approaches used in APDT as a valuable method, extremely effective in
cellular death mediated by the production of reactive species, which can overcome some of the most important problems
of our days, namely the production of resistant or superresistant microorganisms selected over the years by the irrational
use of antibiotics. Another approach presented here describes the basis of a new concept of photobiomodulation on the
wound-healing process. This process increases the rates of tissue repair and, at the same time, acts simultaneously as an
antibacterial and remodeling tissue protocol.
Ravindran Ankathil et al. in Chapter 3, entitled Conspectus on nanotechnology in oral cancer diagnosis and treatment,
present current advances in the field of nanotechnology, and especially the emergence of multimodal nanoparticles that of-
fer the opportunity to develop future strategies significantly toward early diagnosis and more efficient treatment modalities
for oral cancer.
Chapter 4, prepared by Marilene Estanqueiro et al., entitled Lipid-based nanocarriers in cancer therapy, gives an
up-to-date overview about: (1) cancer pathogenesis and treatments; (2) nanocarriers properties that make these systems
advantageous for drug delivery; (3) liposomes and lipid nanoparticles, including their production methods; and (4) a critical
revision of the research work developed under the application of liposomes and lipid nanoparticles in cytotoxic drug delivery.
Chapter 5, entitled Effect of polymer-based nanoparticles on the assay of antimicrobial drug delivery systems, prepared
by Mehmet Gumustas et al., underlines the effectiveness and in vitro/in vivo performance of various antibiotics encapsu-
lated polymer-based nanoparticles in the treatment of infectious diseases. A collection of published papers is summarized
from this perspective, and also comments on targeting microorganisms, advantage, and activity of the developed delivery
system. Properties of analytical techniques for the determination of in vitro and in vivo samples with the validation param-
eters are presented.
Sabyasachi Maiti, in Chapter 6, entitled Nanometric biopolymer devices for oral delivery of macromolecules with clinical
significance, discusses various biological and physicochemical barriers, strategies adopted in augmenting bioabsorption of
macromolecules, and the mechanisms behind their oral transport. A special emphasis is given to the recent developments
in the area of nanobiopolymer devices for effective delivery of macromolecules.
Chapter 7, prepared by Aneta Ostróżka-Cieślik and Beata Sarecka-Hujar, and entitled The use of nanotechnology in
modern pharmacotherapy, reviews the structure, function, and utility of different nanoparticles, especially: nanospheres,
xv
xvi Preface
nanocapsules, nanoliposomes, lipoplexes, lipospheres, dendrimers, fullerenes, carbon nanotubes, nanoemulsions, and nano-
suspensions as potential drug carriers. Advantages and disadvantages of the particular nanostructures are also discussed.
Chapter 8, entitled Nanoparticle system for anticancer drug delivery: targeting to overcome multidrug resistance, pre-
pared by Mohammed M. Safhi et al., focuses on multiple drug resistance exhibited during cancer chemotherapy, and the
influence of nanoparticles research in overcoming this issue.
Ankit Jain and Sanjay K. Jain, in Chapter 9, entitled Application potential of engineered liposomes in tumor target-
ing, sums up the drug targeting potential of the engineered liposomes with contemporary trends in the field of liposomal
research.
Chapter 10, prepared by Rurik K. Salyaev and Natalya I. Rekoslavskaya and entitled Plant-based peroral vaccines,
presents an up-to-date overview about plant derived peroral vaccines and their advantages, in comparison to traditional
vaccines. Their impact in future therapeutics and prophylaxis is also discussed.
Chapter 11, entitled Platelet-rich plasma incorporated nanostructures for tissue engineering applications, prepared by
Mohammad Amin Shamekhi et al., reveals the progress of platelet-rich plasma– and growth factor–incorporated nanostruc-
tures. The authors expose the methodologies to load platelet-rich plasma and growth factors into nanostructures, such as
exploiting heparin-conjugated nanospheres, electrospun nanofibers, graphene (oxide), and nanoliposomes.
Raju Vivek et al., in Chapter 12, entitled Targeted nanotherapeutics based on cancer biomarkers, present a comprehen-
sive overview of collected information of biomarkers-targeted therapeutic nanostructures for cancer nanotherapy.
Chapter 13, entitled Therapeutic nanoparticles for targeted delivery of anticancer drugs, prepared by Neda Alasvand
et al., reviews different types of anticancer drugs and engineering techniques for obtaining efficient delivery systems in
cancer treatment. It also introduces the salient features of this approach, the hurdles that must be overcome, the associated
perspectives, and practical constraints.
Chapter 14 prepared by Biswajit Mukherjee et al., entitled Pulmonary administration of biodegradable drug nanocar-
riers for more efficacious treatment of fungal infections in lungs: insights based on recent findings, focuses on the progress
in the oral delivery of drug nanocarriers, highlighting the pharmacokinetic and pharmacodynamics modulations, their ad-
vantages along the fundamental limitations, and the future perspective based on the recent findings in the field.
Chapter 15, prepared by Walter Ferreira da Silva Júnior et al., entitled Alternative technologies to improve solubility and
stability of poorly water-soluble drugs, summarizes the understanding of solid dispersions, and shows the applicability of
these systems in unconventional systems.
Joana Magalhães et al., in Chapter 16, entitled Oral administration of nanoparticles-based TB drugs, review the uptake
and translocation of drugs in the gastrointestinal tract, the factors that affect drug stability, and other limitations of oral drug
delivery. Additionally, the recent progress in nanodelivery systems for the oral administration of anti-TB (tuberculosis)
drugs and their potential impact are discussed.
Chapter 17, entitled Recombinant lactic acid bacteria secreting OxdC as a novel therapeutic tool for the prevention
of kidney stone disease, prepared by Ponnusamy Sasikumar et al. discusses the potential impact of manipulating gut flora,
with the potential probiotic bacteria that may have a positive impact on gut oxalate levels, and may decrease oxalate ab-
sorption.
Alexandru M. Grumezescu
University Politehnica of Bucharest,
Bucharest, Romania, http://grumezescu.com/
Chapter 1
Selective Effects of Azelaic Acid
in Nanovesicles on Cell Lines
Tritsida Panyosak
University of Phayao, Phayao, Thailand
Chapter Outline
1 Introduction and Historical Background 1 4 Conclusions 5
2 Applications of Anticancer Drug-Loaded Nanovesicles 2 References 6
3 Limitations of Available Therapies: Need of a Novel
Therapeutic Strategy 5
1 INTRODUCTION AND HISTORICAL BACKGROUND
New drug development is a complicated, costly, and time consuming process including preclinical and clinical trials (phase I,
II, and III), applications made for the new drug, and approval from the US Food and Drug Administration (FDA). Enhancing
the safety and efficacy of existing drugs has been attempted by different methods, most importantly by drug delivery at tar-
geted sites. Drug delivery systems could equip extended circulating half-lives so that smaller quantities of a drug are required
for a longer period of time, relieving the patient of side-effects caused by nonspecific tissue uptake, and providing protection
against enzymatic degradation. Often drug delivery systems can select to permeate the cancerous cell and to decrease the
toxicity for normal cell thus the encapsulated cancer drug can decrease the course of therapy. Lipid and nonionic surfactant-
based drug delivery systems have attracted much attention from researchers as potential carriers of various bioactive mol-
ecules that could be used for therapeutic applications. Liposomes and niosomes are nanovesicles that have been widely used
as drug carriers. Liposomes are composed of phospholipids, whereas niosomes contains nonionic surfactants. Niosomes
alleviate the disadvantages associated with liposomes, such as chemical instability, variable purity of phospholipids, and high
cost (Panyosak et al., 2009). The encapsulation of drugs in these vesicular systems offers several advantages, including the
modification of lipophilicity and hydrophilicity, decreasing toxicity, and increasing stability, circulation time, and absorp-
tion of the drug. Many commercial drug delivery systems in the shape of liposomes/niosomes have already been stored with
great success (Panyosak et al., 2007). For example, azelaic acid (AA), a naturally appearing substance, has been shown to
have antimicrobial and anticancer activities (Breathnach, 1999), and it is an attractive drug candidate since it has nontoxic,
nonteratogenic, and nonmutagenic properties. In cell cultures, AA has been shown to exhibit a dose- and time-dependent
antiproliferative effect on several tumor cell lines, such as human cutaneous malignant melanoma, and human choroidal
melanoma. It can penetrate selectively through tumor cells, as compared to normal cells (Breathnach, 1999).
AA can be obtained by oleic acid and nitric acid oxidation, as well as by chemical, physical, or biological oxidation of
free and esterified fatty acids. AA remains in the urine of normal individuals, and in excess in the urine of ketosis patients
and in patients with a congenital component or acquired inability to β-oxidize monocarboxylic acids—dicarboxylic acid-
uria. It lacks acute or chronic toxicity, and it is nonteratogenic and has nonmutagenic effect. As an effect of topical applica-
tion, Breathnach (1999) reported that after application of AA on lesions of primary cutaneous malignant melanoma, this
latter exhibited the clinical regression of lesions, attended by destruction of malignant melanocytes, and return to normal
organization of epidermis and dermis. In vitro, AA is a competitive inhibitor of tyrosinase, the key enzyme that generates
melanocytes. The areas of antitumoral, antibacterial, and antiinflammatory activities have already been successfully ap-
plied to the treatment of acne (Breathnach, 1999). Currently, the FDA has approved finacea (AA) foam, 15%, for the topical
treatment of the inflammatory papules and pustules of mild to moderate rosacea. The approval is based on results from two
pivotal clinical trials examining the efficacy and safety of finacea foam, compared to its foam vehicle (without the drug AA)
Multifunctional Systems for Combined Delivery, Biosensing and Diagnostics. http://dx.doi.org/10.1016/B978-0-323-52725-5.00001-0
Copyright © 2017 Elsevier Inc. All rights reserved. 1
2 Multifunctional Systems for Combined Delivery, Biosensing and Diagnostics
in the topical treatment of papulopustular rosacea (FDA, 2015), and its antipigmentary activity in treating melasma. The
AA effects of antitumor approach will be examined from the viewpoint of its potential as a general antitumoral agent. This
possibility will be investigated, as it could have a role as fundamental therapy, as synergistic therapies, as well as palliative
therapy, by local, oral, or systemic administration in a number of cancer conditions (Breathnach, 1999). In vivo, AA is prob-
ably generated by lipoperoxidation of free and esterified cis-polyunsaturated fatty acids, such as those normally present
in cell membrane phospholipids, and it may act as a natural antioxidant in vivo. In vitro, AA is a competitive inhibitor of
oxidoreductive enzymes, including tyrosinase, enzymes involved in the synthesis of DNA, such as thioredoxin reductase
and DNA polymerase, and oxidoreductases of the mitochondrial respiratory cycle. It is a potent inhibitor of microsomal
5-alpha-reductase, and inhibits anaerobic glycolysis. In vitro, it is a scavenger of toxic oxygen species, especially the toxic
hydroxyl free radical. It also generated inhibitors, inhibiting the generation of reactive oxygen species by neutrophils. Some
of these activities are involved in its antitumoral activities, and it can be administered to humans topically, orally, and in the
form of an AA disodium salt by intrainjection or infusion, intravenously, intraarterially, and intralymphatically. Moreover,
Breathnach (1999) reviewed that prolonging the infusion with successive doses of similar concentration produces sustained
higher serum concentrations over a certain period. It has been evaluated that 90% of maximal uptake should be reached in
the plateau phase of constant infusion of 2.2 g/h, with a maximum cellular (normal) uptake of 0.657 g/h (Breathnach, 1999).
The serum levels achieved are equivalent to 5 × 10–3 mol/L and above, which is the level at which AA has an antiprolifera-
tive and cytotoxic effect on tumoral cells in culture (Breathnach, 1999). However, 60% of administered AA is eliminated in
urine, leaving an unchanged structure within 12 h, and, in the mitochondrial part, is metabolized by β-oxidation via pimelic
and glutaric acids to acetyl coenzyme A. This enters the Krebs cycle, and gives rise to CO , and to malonyl coenzyme A
2
that may be involved in fatty acid biosynthesis. AA generated no toxic metabolites, and crosses the blood-brain barrier. In
culture cells, AA has been exhibited to have a time- and dose-dependent reversible antiproliferative and cytotoxic action
as follows: tumoral cell lines are human cutaneous malignant melanoma, human choroidal melanoma, Harding–Passey
and Cloudman murine melanoma, human squamous cell carcinoma, Raji lymphoma, and leukemia-derived cell lines, and
fibroblastic lines (Breathnach, 1999). AA has been shown to penetrate selectively tumoral cells (HeLa, KB, and B F ), as
16 10
compared with normal cells (Panyosak et al., 2009). The antitumoral effect is connected to DNA synthesis inhibitor, and
may damage mitochondria. AA also affects the karyotype of melanoma cells exposed to subtoxic doses in long-term cul-
ture, selectively affecting undifferentiated cells with a high growth rate and chromosomal abnormalities. It has an effect in
in vitro on plasminogen activator activity, and reduces the fibrinolytic activity of cultured melanoma cells. The fibrinolytic
potential of tumor cells correlates with their respective malignancy, and may play an important role in tumor invasion, pro-
gression, and metastasis (Breathnach, 1999). An antiviral effect has been reported. AA has an antibacterial activity against a
wide range of organisms and, as secondary infection, can be a complication in some tumoral situations. The tumoral situa-
tions in which AA has been used and shown to be effective clinically are melanoma in situ and primary cutaneous malignant
melanoma, and Grade IIIA melanoma with satellitosis. There are reports of a beneficial effect on penile lentiginosis and
reticulate acropigmentation of Kitamura (Breathnach, 1999).
2 APPLICATIONS OF ANTICANCER DRUG-LOADED NANOVESICLES
Medical liposome applications are therapeutic and diagnostic applications. Drugs, makers encapsulated in liposomes, act as
a model, tool, or reagent for basic studies of cell interactions, for the process of recognition and mode of action, but many
drugs have a narrow therapeutic index. However, in various cases, the appropriate drug carriers can reduce the toxicity, or
enhance the efficacy, of drugs. These were explained by pharmacokinetics and biodistribution. The drug–liposome delivery
systems have benefits and limitations that depend on the synergy of liposomes with cells, and their destination in in vivo
after being given drug-loaded nanovesicles in liposomes as route of administration. In addition, both in vitro and in vivo
studies of the interaction with cells have shown that interactions are either simple adsorption or subsequent endocytosis.
Moreover, Lasic (1992) reported that the interaction is an exchange between bilayer and cell membrane, and that liposomes
are rapidly cleared from to the circulation by the macrophages located in liver, spleen, and bone marrow (Lasic, 1992). The
modes of liposome action as drug delivery systems can give several advantages over conventional dosage forms, especially
for parenteral, topical, and pulmonary routes of administration. Liposomes show different biodistribution and pharmacoki-
netics than free drug molecules. Liposomes can be used to improve therapeutic efficacy. The limitations are the retardation
of bioavailability of the drug. Lasic (1995) reported that drug-loaded liposomes have advantages that can be applied as
various dosages, summarized to seven categories, as follows (Lasic, 1995):
1. Improved solubility of lipophilic and amphiphilic drugs. Examples include porphyrins, amphotericin B, minoxidil, pep-
tides, and anthracyclines. Furthermore, hydrophilic drugs, such as doxorubicin or acyclovir, and drug-loaded liposomes
at high concentrations gave solubility several folds over their aqueous solubility (Lasic, 1992).
Selective Effects of Azelaic Acid in Nanovesicles on Cell Lines Chapter | 1 3
2. Passive targeting to the cells of the immune system, especially cells of the mononuclear phagocytic system (reticulo-
endothelial system): examples are antimonials, amphotericin B, porphyrins, and also vaccines, immunomodulators, or
(immuno) supressors (Lasic, 1995).
3. Formulations of liposomal actions, such as sustained release system, or locally administered routes: examples are doxo-
rubicin, cytosine arabinose, cortisones, biological proteins, or peptides, such as vasopressin (Lasic, 1992).
4. Site-avoidance mechanism: liposomes do not set in certain organs, such as heart, kidneys, brain, and nervous system.
This will reduce cardiotoxicity (doxorubicin), nephrotoxicity (amphotericin B), and neurotoxicity (Lasic, 1995).
5. Specific targeting site of liposomes with surface attached ligands can bind to target cells, or can be delivered to the
target tissue by local structural conditions, such as leaky and badly formed blood vessels, and their basal capillaries
(Lasic, 1995).
6. Improve the transfer of hydrophilic, charged molecules, such as chelators, antibiotics, plasmids, and genes into cells
(Lasic, 1995).
7. Improve penetration into tissues, especially in the case of dermally applied liposomal dosage forms. Examples include
anesthetics, corticosteroids, and insulin. Liposome encapsulation is selected to be used as carrier when drugs are very
potent, toxic, and have very short lives in the blood circulation or at the sites of local administration (Lasic, 1995).
Furthermore, Storm et al. (1987) reported that the efficacy was in many cases accommodated because of the decrease in
bioavailability of the drug, especially if the tumor was not a phagocytic system, or located in the organs of mononuclear
phagocytic system. In some cases, such as systemic lymphoma, the effect of liposome encapsulation showed improved
efficacy due to the sustained release effect (Storm et al., 1987) while, in several other cases, the isolation of the drug into
tissues of mononuclear phagocytic system actually reduced its efficacy. Gabizon (1989) presented liposomes in anticancer
therapy, and that many different liposomal formulations of various anticancer agents were shown to be less toxic than the
plain drug (Gabizon, 1989). Doxorubicin has been extensively studied with liposomes. In most cases, the toxicity of drugs
entrapped in liposomes was decreased by about 50%. This includes both short-term and chronic toxicities, because liposomal
encapsulation decreases the distribution of the drug molecules toward many tissues (Gabizon, 1989). Moreover, Lau et al.
(2005) reported that bleomycin that was entrapped in liposomes (bleosome) has been aimed at the treatment of skin cancer.
Free bleomycin in in vitro was shown LD approximately three-fold lower than bleosome on human squamous cell carci-
50
noma (SCC) cells. Furthermore, free drug was shown nearly 30 times lower on human cutaneous keratinocytes (NEB-1)
cells (Lau et al., 2005). In addition, Maswadeh et al. (2002) reported that the cytotoxic and cytostatic activities of the lipo-
some-encapsulated vinblastine were examined against six leukemic human cell lines. The major improvement in vinblastine
retention in buffer, as well as in culture medium, was achieved by employing dipalmitoylphosphatidylglycerol (DPPG). The
50% growth-inhibiting (GI ) and cytostatic activity of liposomal vinblastine did not seem to be affected by the type of the
50
liposome, while the 50% cytotoxic activity (LC ) was affected in four out of the six cell lines tested (Maswadeh et al., 2002).
50
Furthermore, liposomes prepared from lipids isolated from wheat germ were used to examine the percentage of vinblastine
encapsulation, and its capacity into liposomes. The cytotoxic/cytostatic activity of these liposomal formulations has been
examined against nine human leukemic cell lines. The results showed that a remaining percentage of 90% vinblastine in
liposomes. The holding of the drug into liposomes was investigated and found to be time-dependent at 37°C. Liposomes
loaded with vinblastine showed a mean of LC at 124.6 nM, and mean of GI at 30.8 nM (Maswadeh et al., 2000). On the
50 50
other hand, Sharma et al. (1995) showed that taxanes, such as paclitaxel and docetaxel, act against ovarian cancer and other
malignancies, while SB-T-1011, a taxane semisynthetic form, shows similar or greater in vitro cytostatic activity than pacli-
taxel, depending on the tumor cell line. The administration of taxanes is problematic because of their low solubility in most
pharmaceutically agreeable solvents. This formulation used clinically contains cremophor/ethanol or polysorbate 80/etha-
nol, excipients that may cause serious adverse effects; meanwhile, in order to eliminate these vehicles, Sharma et al. (1995)
have prepared paclitaxel liposome formulations. Antitumor activity was evaluated against A121a, a taxane-sensitive human
ovarian (subcutaneous xenografts) tumor, growing as in athymic nude mice. Free taxane and taxane entrapped in liposomal
formulations showed similar antitumor effects. The antitumor activity of paclitaxel and SB-T-1011 was similar, and docetax-
el was more potent than either paclitaxel or SB-T-1011. On the whole, taxane liposomes were better and more easily
tolerated via intravenous administration than taxane formulated in cremophor/ethanol (Sharma et al., 1995). Although the
clinical formulation of paclitaxel is an important anticancer agent, it has significant side-effects, few sides of which are re-
lated to its formulation in cremophor/ethanol. Paclitaxel is difficult to formulate for intravenous administration since its
structure is partly hydrophobic. However, Sharma et al. (1997) reported the therapeutic effects of two liposome formulations
of paclitaxel against human tumor (ovarian A121) growing subcutaneously (xenograft in athymic nude mice). The liposome
formulations used were ETL and TTL; the ETL formulation was composed of a single lipid, egg phosphatidylcholine (PC),
and the TTL formulation was composed of a mixture of 3 lipids: di-elaidoyl PC, di-myristoyl, PC and 1-stearoyl,2-caproyl
PC. TTL was used as a stable aqueous suspensions or as a reconstituted form of lyophilisation, while ETL was used as a