Sunday, June 13, 2021

Design Consideration—Using Nanoparticles for Drug Delivery

The development of drug delivery systems entails a wide range of tasks familiar to the engineer: the development of materials suitable to the specific application (biodegradable, pH-sensitive, anionic, flexible, etc.), the attainment of a particular degree of drug loading and type of release kinetics (slow, fast, pulsatile), and proof of efficacy.

To apply nanoparticle systems in drug delivery technology, there are many design considerations which will be discussed in the article.


Design Considerations of a Drug Delivery System


Drug delivery is the method of administering a bioactive compound to achieve a therapeutic effect, in humans or animals. Drug delivery systems are formulations that modify the drug release profile and the ability to cross biological barriers, the biodistribution and pharmacokinetics, improving its efficacy and safety, as well as the patient compliance.

The general design considerations for a drug delivery system include:
  • Potential interaction with tissues and cells
    • Biocompatibility of drug delivery carriers is crucial regarding the nature of their interaction with surrounding tissues
      • It is important to remember that the drug itself can have important effects on the biocompatibility of a drug delivery system, particularly for formulations that involve a stationary depot.[43]
    • There may be unanticipated interactions between the drug delivery system and drug, affecting tissue reaction.[43]
      • Generally, the evaluation of a formulation's biocompatibility progresses through in vitro and in vivo phases.
    • There are many approaches to mitigating tissue reaction, all of which could affect biocompatibility, such as altering surface micro- or nanostructure,[52] and surface modification.
      • One surface modification that has an important impact on drug delivery is PEGylation – the decoration of particle surfaces with polyethylene glycol (PEG) – which reduces particle interaction with the reticuloendothelial system and therefore increases circulation time. Its effect on tissue reaction is less well understood.[54]
  • Potential Toxicity and side effects
    • One should be particularly suspicious of drugs with extremes of pH, hydrophobicity, osmolarity; compounds with known cytotoxic effects including solvents and surfactants; and reactive moieties.
      • These concerns also apply to carriers for the drug delivery system, drug breakdown products, drug preservatives if any, and other putatively inert excipients.
    • Need to develop materials suitable to the specific application—biodegradable, pH-sensitive, anionic, flexible, etc.
      • Biodegradability is essential to avoid organ accumulation, potentially leading to toxicity and other undesirable side effects.[55,56]
  • Biodistribution of drugs and targeting
    • Carriers should have the ability of overcoming physiological barriers in the process of transporting and releasing the drug to the targeted cells or tissues
    • To attain a particular degree of drug loading and to select the type of release kinetics (i.e., slow, fast, pulsatile), a good drug delivery system should be capable of:
  • Drug loading and release
    • Drug loading and release control how drugs are available to cells and tissues over time and in space.
    • Besides degradation physical means such as heating and light may be used to provoke the therapeutic effect (cell death) or for local drug release, respectively.
      • Smart drug delivery systems can respond to external stimuli like temperature, pH, light, magnetic and electric fields, ionic strength, or enzymatic environment.
    • There are numerous parameters that can alter release kinetics, which are markedly affected by carrier's size, because of the differences in surface area to volume ratios.[53]
    • Conjugation of drugs to macromolecular carriers is a proven strategy for improving pharmacokinetics.
      • In one approach, the drug is covalently attached to a long-lived circulating macromolecule—such as PEG—through a linker that is slowly cleaved to release the native drug.
  • Formulation stability and shelf life
  • Achieving the expected therapeutic effect
    • Controlled and sustained drug release at the target site, improving the therapeutic efficacy and reducing side effects.

Nanoparticle Formulations for Drug Delivery


Nanotechnology is the source of exciting progresses in the drug delivery field, offering suitable means for site-specific and time-controlled delivery of small molecular weight drugs, proteins, peptides, oligosaccharides, vaccines and nucleic acids.[46-50]
The reason why these nanoparticles (NPs) are attractive for medical purposes is based on their important and unique features, such as their surface to mass ratio that is much larger than that of other particles, their quantum properties and their ability to adsorb and carry other compounds.
It could bring significant advances in the diagnosis and treatment of disease. Each kind of formulation has characteristic drug loading capacity, particle and drug stability, drug release rates, and targeting ability.
A multitude of substances are currently under investigation for the preparation of NPs for drug delivery, varying from biological substances like albumin, gelatin and phospholipids for liposomes, and more substances of a chemical nature like various polymers and solid metal containing NPs.[40]
The general design considerations for a nanodrug delivery system include:
  • Potential interaction with tissues and cells
    • Small drugs may diffuse through the capillary walls into the tissues. Otherwise, nanoparticles transport occurs through compromised endothelial barrier or mediated by specific transport systems.
      • Tumor tissues have an increased capillary permeability, which allows a high rate of NPs accumulation, based on the “enhanced permeability and retention” (EPR) effect.[57]
      • NPs circulating in the bloodstream are normally able to penetrate the tissues through a paracellular path only at restricted sites, where the capillaries have open fenestrations, as in the sinus endothelium of the liver, in the tumor neovasculature[58] or when the endothelial barrier is altered by inflammatory processes (e.g., rheumatoid arthritis, infections).[59]
  • Potential Toxicity and side effects
    • The biological consequences of NPs are not well understood, but are potentially significant, given their enhanced capability to enter cells compared to larger particles – hence the burgeoning field of nanotoxicology.[43]
    • The potential toxicity, greatly depends on the actual composition of the NP formulation.
      • The toxicology of particulate matter differs from toxicology of substances as the composing chemical(s) may or may not be soluble in biological matrices, thus influencing greatly the potential exposure of various internal organs.
      • Biodegradable NPs with a limited life span as long as therapeutically needed would be optimal.
    • Using NPs to deliver drugs, it is said that it can reduce the toxicity and side effects of drugs
      • However, safety evaluation of the NP formulations for drug delivery is still important.
  • Biodistribution of nanodrugs and targeting
    • Local nanodrug delivery or drug targeting results in increased local drug concentrations and provides strategies for more specific therapy.
    • NP size can influence the NP distribution. Even small size differences may be of influence for the actual distribution and thus bioavailability.[60-62]
    • The ability of nanodelivery systems to overcome physiological barriers is determined by properties such as particle size, surface charge and hydrophobicity.
      • For NPs the situation is different as their size opens the potential for crossing the various biological barriers within the body. In addition, the nanosize also allows for access into the cell and various cellular compartments including the nucleus.
      • From a positive viewpoint, especially the potential to cross the blood brain barrier may open new ways for nanodrug delivery into the brain.
  • Drug loading and release
    • NPs have a relatively large (functional) surface which is able to bind, adsorb and carry other compounds such as drugs, probes and proteins.
    • NPs may be used for selective release of the content based on different external stimuli (e.g., temperature, pH, etc.) after specific localization.
  • Formulation stability and shelf life
    • The surface charge of NPs is important as it determines its
      • Stability
      • Propensity to aggregate in the bloodstream
      • Interacting with the cell membranes.
  • Achieving the expected therapeutic effect
    • The aims for NP entrapment of drugs are either enhanced delivery to, or uptake by, target cells and/or a reduction in the toxicity of the free drug to non-target organs. Both situations will result in an increase of therapeutic index, the margin between the doses resulting in a therapeutic efficacy (eg, tumor cell death) and toxicity to other organ systems.

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