Drug release from Nanoparticles

Farmaco convenzionale

Oral intake

or hyperglycosilation

1. Prodrugs to increase lipophilicity

Lin JH Pharmacol. Rev. 1997

When a pharmaceutical agent is encapsulated within, or attached to, a polymer or lipid, drug safety and efficacy can be greatly improved and new therapies are possible.

• Drug targeting is concerned with modulation and control of the biodistribution of a drug based on a suitable delivery system.

• The biodistribution of the drug is not governed by the drug itself but by the delivery system.

• The biomedical design of the delivery system depends on the properties of the target in combination with those of the drug and the needs of the patient.

(Source: ISI Web of Knowledge ©)

2000-2013

Temporal evolution in the number of scientific papers publishedinvolving drug delivery using nanoparticles.

Search terms: ‘drug delivery’

Search terms: ‘drug delivery’ and ‘nanoparticles’

10901302

14441716

1978

24592710

3173

4520

446

64 84 124 153 209364

525686

1175

0

500

1000

1500

2000

2500

3000

3500

4000

4500

5000

2000 2001 2002 2003 2004 2005 2006 2007 2008 2009

2013 = 2379

Potential advantages of improved drug delivery:

Ability to target specific locations in the body• Reduction of the quantity of drug needed to attain a particular concentration in thevicinity of the target;• Decreased number of dosages and possibly less invasive dosing• Reduction of harmful side effects due to targeted delivery (reduced concentration of the drug at non-target sites); Facilitation of drug administration for pharmaceuticals with short in vivo half-lives (for example peptides and proteins).

Advantages must be weighed against the following concerns in the developmentof each particular drug-delivery system: 1. toxicity of the materials (or their degradation products) from which the drug is

released, or other safety issues such as unwanted rapid release of the drug (dose dumping);

2. discomfort caused by the system itself or the means of insertion;3. expense of the system due to the drug encapsulation materials or the manufacturing

process.

METHODS OF DRUG DELIVERY

•epicutaneous (application onto the skin). the active substance diffuses through skin in a transdermal route.•intradermal, (into the skin itself) is used for skin testing some allergens, and also for mantoux•subcutaneous (under the skin), e.g. insulin•nasal administration (through the nose)•intravenous (into a vein), e.g. many drugs, total parenteral nutrition•intraarterial (into an artery), •intramuscular (into a muscle), e.g. many vaccines, antibiotics, and long-term psychoactive agents. •intracardiac (into the heart), e.g. adrenaline during cardiopulmonary resuscitation (no longer commonly performed)•intraosseous infusion (into the bone marrow) is, in effect, an indirect intravenous access because the bone marrow drains directly into the venous system•intrathecal (into the spinal canal) is most commonly used for spinal anesthesia and chemotherapy•intraperitoneal, (infusion or injection into the peritoneum) e.g. peritoneal dialysis•Intravesical infusion is into the urinary bladder.•intravitreal, through the eye

NP drug delivery systems

Possible mechanisms by which drugs are released:

1. Diffusion of the drug species from or through the system.

2. A chemical or enzymatic reaction leading to degradation of the system, or cleavage of the drug from the system.

3. Water activation, either through osmosis or swelling of the system.

Rosen H & Abribat T, Nature Reviews 2005

DIFFUSION

Drug release by swelling and erosion

Ways of controlling drug release locally:

Smart Stimuli-responsive NPs

Stimuli-responsive NPs show a sharp change in properties upon a small or modest variations of the environmental conditions such as temperature, light, salt concentration or pH. Different organs, tissues and cellular compartments may have large differences in pH, which is considered the most suitable stimulus.

This behavior can be used for the preparation of so-called ‘smart’ drug delivery systems, which mimic biological response behavior to a certain extent.

Schmalijohann D., Adv. Drug Deliv. Rev, 58 2006

Ways of controlling drug release locally

• pH• Light• Thermally • Ultrasound • Magnetically• Enzyme-induced

pH in living systemsCompartment pH

Gastric acid1Lysosomes4.5Granules of chromaffin cells5.5Human skin5.5Urine6.0

Cytosol7.2Cerebrospinal fluid (CSF)7.5Blood7.34–7.45Mitochondrial matrix7.5Pancreas secretions8.1Solid tumours 6.5

HYDROGELSPolymers or co-polymers (e.g. acrylamide and acrylic acid) create water-impregnated nanoparticles with pores of well-defined size. Water flows freely into these particles, carrying proteins and other small molecules into the polymer matrix. By controlling the pore size, huge proteins such as albumin and immunoglobulin are excluded while smaller peptides and other molecules are allowed. flexibility

Polymer-based hydrogels

Biodegradable and Biocompatible Polymers

• PolyAlkylCyanoAcrylate

PLGA

chitosan

CH2OH

Targets for chemical modification

Poly-hydroxy-ethil-metacrylate

Hydrogel formation

Ionic hydrogels

Hoffman AS, Adv Drug Deliv Rev, 2002

egg box structure

Hydrogels from hydrophobic polymers

Hydrogels are three dimensional networks of polymers

Hydrogels as Drug Delivery SystemsHydrogel Requirements:Controlled or delayed diffusion of moleculesPore size compatibility with the biological moleculeSolubility of the biological molecule

Release characteristics are dependenton the chemical nature of the hydrogel

orally delivered insulin

C.B. Woitiski et al. Eur. J. Pharm. Sci. 41 (2010) 556

pH Sensitive HydrogelsR

R

NH3+

NH3+

N Hydrophobic side chain

O

R

R

NH2

NH2

N Hydrophobic side chain

O

pH<6.5 buffer pH>6.5 bufferR= polymer backbone

Crosslinking is based on hydrogen bonding, and secondary hydrophobic interactions.Crosslinking is reversibleControl over the pore sizes

Wang J Colloids Surfaces B. 2014

pH-responsive POLYMERIC NP

Schmalijohann D., Adv. Drug Deliv. Rev, 58 2006, Oh K.T. et al., J. Mater Chem, 17, 2007

Ionizable polymers with a pKa value between 3 and 10 are candidates for pH-responsive systems.

Poly(ethylene imine) (PEI) linear or branched

Poly(L-lysine) (PLL)

The change of pH triggers the passage from ionized to un-ionized form or vice versa

“proton sponge” hypothesis

pH-sensitive liposomes

liposomes can either remain bound at the cell surface, disassociate from the receptor, or accumulate in coated or non-coated invaginations. Following endocytosis (a), can be delivered to lysosomes (c) where may be degraded by lysosomal peptidases and hydrolases. Following acidification of the endosomal lumen, pH-sensitive liposomes are designed to either fuse with the endosomal membrane (e), releasing their contents directly into the cytoplasm, or become destabilized and subsequently destabilize the endosomal membrane (d) resulting in leakage of the endosomal contents into the cytosol.

pH-sensitive liposomes for intracellular drug delivery

Liposomes containing cationic lipidsescape the lysosomal pathway

DOPE (phosphatidylethanolamine)

-NH2 -NH3+

DOPE

Guo X et al. Biophys. J. 84(3) 1784–1795

pH-sensitive liposomesFrom lamellar to hexagonal phase transition

Drug release

pH-sensitive polymersomes

degradation of the block

copolymer

Drug release

Cleavage of pH-Sensitive Bonds

blue, hydrophilic block; red, groups responsible for the dissolution

Meng et al. Biomacromolecules, Vol. 10, No. 2, 2009

pH-Induced Solubility

dissolution of the

polymersome

37°C41°C

Dipalmitoyl (C16) phosphatidylcholine

Thermally sensitive phospholipids

41°C

H. Grüll, S. Langereis / J Control Release 161 (2012) 317–327

Thermo-responsive POLYMERS in drug deliveryTemperature-responsive polymers and hydrogels exhibit a volume phase transition at a certain temperature, which causes a sudden change in the solvation state.

Poly-N-IsoPropylAcrilAmide (PNIPAM) is the most prominent candidate as thermo-responsive polymer.

PNIPAM copolymers have been mainly studied for the oral delivery of calcitonin and insulin.

Schmalijohann D., Adv. Drug Deliv. Rev, 58 2006M.Nakayama et al. Material Matters 2010

LCST: lower critical solution temperature UCST: upper critical solution temperature

Microwaves

39°C

41°C43°C

39°C

39°C

Ultrasound-triggered drug delivery systemsNon-invasively transmitted energy through the skin can be focused on a specific location and employed for enhanced drug release.

Elastin-like polypeptide

PluronicTriggering mechanism: Enhanced cavitation activity

O/W Emulsions

The o/w submicron LEs has many appealing properties as drug carriers. They are biocompatible, biodegradable, physically stable and relatively easy to produce on a large scale using proven technology.

Tamilvanan S., Prog Lipid Res, 43, 2004

Date A.A., Adv. Drug Deliv. Rev, 59 2007