artigo 3_ developing nanoparticle drug carriers

13/2/2014 Pharmaceutical Technology: Developing nanoparticle drug carriers

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January 1, 2007

Developing nanoparticle drug carriersBy Christine Vauthier,Patrick Couvreur

The development of nanoparticulate drug carriers has followed several routes depending on thefinal application. Although a wide variety of systems have been designed with their ownadvantages and limitations, the common goal is to rationalize drug delivery to enhance thebioavailability of the drugs towards targeted diseased cells, promoting the required response whileminimizing side-effects. Nanoparticulate drug carriers also represent unique opportunities to getchallenging molecules, such as nucleic..

Nanoparticulate drug carriers include a class of particles made of polymers or lipids that — because of their sizeand chemical composition —permit systemic and local treatment.

In general, these systems are expected to protect a drug from degradation, enhance drug absorption by facilitatingdiffusion through epithelium, modify the pharmacokinetic and drug tissue distribution profile and/or improve

intracellular penetration and distribution. 1–3

They can be administered by all possible routes of administration, generally improving

both bioavailability and therapeutic efficacy of the carried drug. 3 They represent analternative class of vehicles to liposomes to transport drugs straight to the targeteddiseased cells in the body.

Numerous types of nanoparticle drug carriers have been developed (Table 1). The

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Table 1 Definition of the different

types of nanoparticulate drug

carriers and schematic

representations. 4–18

Table 2 Suggested nanoparticulate

drug carriers as a function of the

physicochemical characteristics of the

drug to be administered. 3–31

range of applications includes the treatment of all major public health diseases includingsevere infections and cancer. They are also strongly believed to potentially solve theproblem of the in vivo delivery of biomimetic molecules such as nucleic acids, proteins,peptides and very insoluble drugs, which is very difficult by other means (Table 2).

Although several liposomal formulations have been marketed since 1995 — illustratingthat nanotechnology can be used to administer toxic drugs such as antifungal andanticancer agents — two new formulations for polymer nanoparticles entered clinicaltrials recently for cancer therapy.

This article focuses on the development of nanoparticulate drug carriers, highlighting several of the key issuesbeing addressed up to now.

Design

The design of nanoparticulate drug carriers must fulfil the following requirements:

Composition must be acceptable for use in human therapy (biodegradable,biocompatible, nontoxic).Size must be suitable for administration to humans by different routes and allowdiffusion inside the body to reach the biological target site.The biodistribution should suit the therapeutic target.The carrier must be loaded with the drug and should only release the drug in a controlled manner once thecarrier has reached the biological target site.

Composition

As lipids are part of living constituents, they were considered to be suitable chemicals to formulate solid lipidnanoparticles (SLNs) and nanocapsules (LNCs) (Tables 1 and 2).

Synthetic polymers offer an almost infinite array of chemical composition and structure combinations. However, onlya few have the requirements that make them useful as nanoparticulate drug carriers.

The prime candidates are polyesters including polylactide (PLA) derivatives and polyepsiloncaprolactone (PCL),polyalkylcyanoacrylate (PACA) and corresponding copolymers with polyethylene glycol (PEG), polysaccharides andpolyethylenimine (Tables 1 and 2).

Natural macromolecules including polysaccharides (chitosan, alginate, pectine) were introduced to formulatehydrogel nanoparticles. Research is continuing to find suitable new polymers because polymers can be produced at

lower cost than lipids and should be more interesting (economically) based on economic considerations. 32

Polyesters of polymalic acid, polyamino acids of polybenzyl-glutamate) and pH- or temperature-sensitive species

are growing in popularity. 33–37

Size requirements and synthesis methods

Whatever the material constituting the drug delivery device, the second requirement is to produce particles smallenough to diffuse across biological barriers encountered in the body to transport the drug from the administrationsite down to the target tissue and/or cells. Considering the mucosal route, the smaller the nanoparticles, the better

they can transport drugs across mucosa. 28,38

After intravenous administration, particles with a diameter less than 100 nm are generally less recognized bymacrophages of the host defence system (macrophage of the mononuclear phagocyte system [MPS]) and cancirculate for several hours in the blood stream. Their small size also promotes their diffusion through fenestration of

the altered blood vessels found in diseased tissues. 2

The various methods developed to prepare nanoparticulate drug carriers have been reviewed in several papers.11,12,17 The principle of the methods depends on the type of particles to produce, the raw material and the drug tobe encapsulated. The diameter of the particles produced is generally below a few hundred nanometers.

The methods are reproducible and most of them can easily be scaled up to be industrialized (i.e., nanoprecipitationproducing nanocapsules, anionic emulsion polymerization producing PACA nanoparticles, production of SLNs).



Continuous processes also exist to produce nanoparticles by nanoprecipitation and SLNs. 39 Emerging methodsinclude environmental-friendly procedures based on the self-assemblage of macromolecules in aqueous solutions,gelation of hydrophilic gelling polymers, formation of lipid nanoparticles and nanocapsules, emulsion polymerizationof pure monomers in a water continuous phase and methods using supercritical fluid carbon dioxide as the solvent.40–42

Biodistribution control

Reaching the ultimate goal of drug targeting requires that the fate of the nanoparticulate drug carrier will beperfectly controlled in vivo. This requires a specific design of the particle. As previously discussed, particle size isone parameter to consider.

Apart from the size criteria, the biodistribution of particles is greatly influenced by the interactions occurring betweenbody components and the nanoparticle surface. Thus, another important factor includes the composition of thenanoparticle surface. For instance, coating nanoparticles with PEG reduces the opsonization on their surface hence

the uptake by the MPS after intravenous administration. 2,18,43

Thus, PEG-coated nanoparticles (i.e., 'Stealth' nanoparticles) remain in the blood for several hours while theiruncoated counterparts accumulate in the MPS within a few minutes following administration. Recently, it was shownthat the conformation of chains of macromolecules grafted on the nanoparticle surface also influences the

interaction with blood components. 44 Thus, depending on the coating material and conformation, it is now possibleto suggest several general rules to design nanoparticles that deliver drugs either to macrophages of the MPS or

outside the MPS area. 2,3,34,45

Nanoparticles escaping the MPS uptake can be used to retain drugs in the blood compartment or to distributetherapeutic compounds in tumoural or inflamed tissues thanks to the local enhanced permeation retention effect

occurring in diseased tissues. 46 The specificity of recognition of the target cells by the nanocarriers requires a

subsequent sophistication of labelling address, which must be attached on the nanoparticle surface too. 19,45–47

Convincing results of targeting were obtained by coupling monosaccharides or folate residues on the

nanoparticulate drug carrier surfaces. 17,48–51

Other strategies are based on the covalent attachment of the biotin-binding protein, NeutrAvidin, enabling the

binding of biotinylated drug-targeting ligands such as antibodies by avidin–biotin complex formation. 52 Morerecently, specific nucleic acids named aptamers were considered for targeted delivery and uptake of nanoparticles

in a cell-specific manner. 53

It can be expected that the extension of the targeting strategy will progress further with new data from the biologistsidentifying possible specific target receptors on cell surfaces and corresponding ligands, and from progress in

molecular imprinting techniques. 54

For oral or nasal administration, the use of chitosan as a coating material of the nanocarrier surfaces may promotethe bioadhesive properties of the drug delivery device on the mucosa, hence promoting absorption of drugs by the

epithelium. 55–56

Incorporation of drugs

Many methods of nanoparticle preparation were developed because it is quite a challenge to incorporate a druginto a nanocarrier (Table 2). Most lipophilic small molecules (such as indomethacin, amphotericin B, paclitaxel)could be encapsulated into PLA, PLGA and PCL nanoparticles, in SLNs, in LNCs and in polymer micelles.

Macromolecular drugs including therapeutic peptides and nucleic acids were successfully encapsulated innanogels. Nucleic acids can be incorporated in nanocarriers by forming polyelectrolyte complexes with polycationssuch as polyethylene imine and chitosan.

Nanoparticles made of PACA accept various types of drugs because of the wide variety of systems being producedwith this polymer. Small molecules were encapsulated in nanospheres whether they were hydrophilic (ampicillin,doxorubicin) or poorly soluble (saquinavir, paclitaxel). Peptides including insulin and human growth hormone wereencapsulated in oil-containing nanocapsules and in nanospheres, respectively, whereas nucleic acids wereencapsulated in water-containing nanocapsules.

The encapsulated or entrapped drug should be released from the carrier only when it will reach the biological

target. 45,58 Indeed, the main difficulty is to keep the drug inside such small carriers because of the enormousexchange surface with the surrounding external media. Thus, the release of the drug often occurs as a burst assoon as the drug-loaded nanocarrier is transferred in a releasing media.



Table 3 Mode of administration of

nanoparticulate drug carriers and

therapeutic applications. 3

Key points

This phenomenon can be reduced bycomplexing the drug with components of the carriers 59 or by forming a

hydrogel barrier at the carrier surface. 45 Temperature- and pH-sensitive systems are another option to provide

drug release on demand. 10,33,37 Molecular imprinting techniques may soon provide interesting matrices that are

able to retain drugs inside the nanospheres, eventually triggering the release using an external stimulus. 54

Potential applications

Nanoparticulate drug carriers represent a platform to deliver numerous drugs used inthe treatment of major health threats such as cancers, infections (i.e., HIV, malaria,tuberculosis), metabolic diseases (such as diabetes and osteoporosis) andautoimmune diseases (glaucoma, for example). Different routes of administration maybe used (Table 3). Other potential therapeutic applications concern the management

of graft rejection, inflammation and pain. 3

Each case represents a huge number of patients and an enormous potential market.Nanoparticulate drug carriers offer the opportunity to overcome many of the deliveryproblems encountered with old and new therapeutic compounds.

Nanoparticulate drug carriers will be important for the administration of molecules thathave high therapeutic potential, but currently produce severe side-effects. Becausenanotechnologies allow a more precise delivery of the therapeutic compound to the target cells, they may alsoreduce drug concentrations in healthy organs and tissues. The improvement of drug delivery minimizing the side-effects has been proved in treatment of cancer with doxorubicin and of infections with amphothericin B or

halofantrine. 4,45,59,60

The use of nanoparticulate drug carriers can also help to solve the problems of drugs coming out from thediscovery pipelines, which often present special delivery challenges. Many of them are poorly soluble compounds,which results in limited bioavailability with low and/or erratic absorption when using traditional pharmaceuticalformulations.

This is, for example, the case of paclitaxel, a lead molecule in cancer therapy. Nanoparticulate formulations ofpaclitaxel have avoided the use of the excipient Cremophor (responsible for severe side-effects), which

considerably limited the conventional treatment. 23 Interesting results were also obtained considering the oral

administration of nanoparticulate formulations of poorly soluble compounds (paclitaxel, saquinavir). 7,20,37,59

The oral route is importantly considered for the administration of drugs as it is preferred by patients, results in abetter treatment compliance, and is safer and less expensive than the other administration routes.

The enormous therapeutic potential of proteins, peptides, genes, antisenseoligonucleotides or small-interfering RNA, which all represent an important potentialmarket, depends on the success to find suitable carriers that will bring them to theirintracellular target site. Peptides and proteins could be delivered in vivo through

mucosa using nanoparticulate drug carriers, 55 which was very challenging iflooking to the difficulties encountered by macromolecules to cross mucosalepithelia and to resist the hashed conditions found on mucosa.

Considering nucleic acids, literature already provides several convincing examplesof nanoformulations allowing antisense oligonucleotides or small-interfering RNA to

be better delivered in vivo. 9,10,12,61

Another challenge concerns the delivery of drugs to chemoresistant cells. This includes one of the mainachievements of nanoparticulate drug carriers in cancer therapy with the very promising Phase I/II clinical trial for

the treatment of hepatocellular carcinoma using Doxorubicin Transdrug. 27 Doxorubicin Transdrug is doxorubicinloaded onto polyisohexylcyanoacrylate nanoparticles that were granted orphan drug status by the EuropeanAgency for the Evaluation of Medicinal Products (EMEA) in Europe and by FDA. The Transdrug nanotechnology is

able to deliver, intracellularly, a therapeutic concentration of doxorubicin in chemoresistant cancer cells. 27,62

Issues for using nanoparticulate drug carriers can be the repacking of a known drug to extend its life cycledeveloping new formulations with better performance or finding new therapeutic indications. This is part of a lowrisk/high reward research strategy in the development of drugs as the very high risk inherent to the discovery ofnew chemical entities is generally recognized and the development process can remain focused on deliveryproblems only.

As discussed before regarding paclitaxel, another motivation for repacking a drug is that it requires the association



of excipients responsible for dramatic side-effects. This leads to the other key achievement in the development ofnanoparticulate drug carrier with a new formulation of paclitaxel as albumin nanoparticles (ABI007 or Abraxane;American BioScience Inc., Santa Monica, CA, USA) devoid of cremophor and which can be administered withoutprevious treatments with steroids. After the success of the Phase III clinical study, this new formulation was

registered in the US and is now proposed as a taxane alternative in metastatic breast cancer treatments. 23,63

Conclusion

Nanoparticulate drug carriers are interesting drug delivery devices for systemic or local treatments and can beadministered by all possible routes of administration. Although, as yet, there is not a unique and perfectnanocarrier, a number of studies suggest that each of those already developed have their own interest to improvedrug efficacy/safety and can be used to revisit drug delivery methods.

The possibility of making tailor-made nanocarriers will revolutionize the in vivo delivery of drugs. Several deliveryplatforms may emerge in the future, each including either a type of drug (i.e., peptides or nucleic acids) or a specificbiodistribution. The new treatments will definitively improve both specificity and precision of drug delivery.

Christine Vauthier is director of research at the Centre National de la Recherche Scientifique, France.

Patrick Couvreur is a professor at the University of Paris Sud (UMR CNRS 8612), France.

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Table 1 Definition of the different types of nanoparticulate drug carriers and schematic representations. 4–18 Table 2 Suggested nanoparticulate drug carriers as a function of the physicochemical characteristics of the drug to be administered.

3–31 Key points



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Table 3 Mode of administration of nanoparticulate drug carriers and therapeutic applications. 3

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