Biopharmaceutical Parameters to Consider in Order to Alter the Fate of Nanocarriers after Oral Delivery

Emilie Roger; Frederic Lagarce; Emmanuel Garcion; Jean-Pierre Benoit

Nanomedicine. 2012;5(2):287-306.

Conclusion & Future Perspective

There are two main challenges of drug delivery via the oral route:

To enhance the bioavailability of drugs;
To target distant pharmacological receptors after absorption.

To address the issue of bioavailability, the integrity of the nanocarriers is not requested. One of the best example was shown by Leroux et al. with Eudragit L100–55 nanoparticles, which released the drug CGP 57813 instantly at pH 5.5 and increased its relative bioavailability in comparison to Eudragit S100 particles displaying a slower dissolution rate.^[196] Moreover, the formulation of bioadhesive nanoparticles help them to remain in the GI tract and locally release the encapsulated drug, thus providing a better probability for absorption. As stated by the biopharmaceutics classification system,^[197] the most important parameters to consider for absorption are permeability and dissolution rate of the drug. As shown in the present paper, nanocarriers can have a significant impact on these properties. For a drug belonging to biopharmaceutics classification system class II (high permeability, low solubility) or class IV (low permeability, low solubility), the dispersion of the drug in nanosized drug delivery systems is a solution to enhance absorption, effectively and with relative simplicity. As a matter of fact, in this case the carrier has not to be functionalized using surface treatment. To increase the permeability, the positive charge and the nature of the nanocarrier seem important to consider in combination with molecular moieties that will serve for specific recognition and transport. PEG, PLGA and chitosan coatings have been used with success for enhancing permeability and uptake via enterocytes. Tomato lectins and WGA are promising ligands to facilitate the uptake by enterocytes. Further work is required to identify specific targets on the surface of the enterocytes that will increase the internalization of the carrier or the encapsulated drug in the cells.

The second challenge is to target distant pharmacological receptors via the oral route. In this case the integrity of the nanocarrier has to remain to provide specific properties such as stealthiness, controlled release of the drug, targeting of the organs. To date, no such nanoparticles have been described. Indeed, this tricky issue is to formulate a nanovector able to resist the stress of GI tract while also being capable of transcytosis and finally being able to avoid or resist the destruction by the liver during the first-pass effect. In this paper, different components able to resist the physicochemical stress have been reviewed (PEG, PLGA and chitosan). They display complementary properties and can be mixed to obtain optimal behavior. The main issue is transcytosis through enterocyte. The cellular trafficking of nanocarriers across enterocyte is poorly documented and appears to be critical in the design of new active nanovector for the oral route. For example, those carriers need to escape lysosomal degradation and avoid recycling endosomal pathways. Thus, among the described pathways, the caveolae endocytosis reaching caveosomes, appears to be the most appropriate. Unfortunately, the specific ligands to target this pathway remain to be discovered.

Even if a ligand is found, the problem remains very complex. For example, vitamin B12 recognize a glycoprotein called cubulin on the surface of enterocyte to proceed to transcytosis.^[198] As this mechanism may be interesting for transcytosis targeting through nanocarrier across enterocytes it may also alter targeting within the blood due to recognition signal (initially for cubulin) used on their surface.

Thus, one of the main problems with nanocarrier design remains in the fact that intrinsic properties that may help to cross GI barrier may also significantly alter further behavior in the blood.

Until recently, oral drug delivery was mainly assessed on the basis of overall drug permeability through the GI epithelium. Bioavailability was the main issue to address. Currently, designing the 'magic bullet' for the oral route is the next milestone to reach. Using smart nanocarriers able to improve solubility of drug while conveying them to specific targets involves rationalization of their behavior within specific GI micro- or nano-environments to determine the exact relevance for each of them. Although the overall idea is not necessarily to keep full integrity of the nanocarrier used for oral drug delivery, as drug bioavailability might be improved independently, keeping properties of nanocarriers as if they were used through the blood pathway represent a great advantage.

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Financial & competing interests disclosure
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
Writing assistance was utilized in the production of this manuscript.

Cite this: Biopharmaceutical Parameters to Consider in Order to Alter the Fate of Nanocarriers after Oral Delivery - Medscape - Dec 31, 2012.

Table 1. Examples of nanocarrier formulations that increase the oral bioavailability of drugs.
Formulation	Drug	Oral bioavailability of the drug alone	Increased oral bioavailability with formulation	Ref.
SLN®	Clozapine	<27%	4.5-fold	^[2]
SLN	Quercetin	<1%	>fivefold	^[3]
SLN	Nitrendipine	Ranging from 10 to 20%	Three- to four-fold	^[4]
SLN	Vinpocetine	<50%	4.16 to 4.17-fold	^[5]
Poly(alkyl cyanoacrylate) NPs	Vincamine	22 ± 1%	Nearly twofold	^[6]
CS-NPs	Cyclosporin A	10–60% with high variability	2.6-fold	^[7]
LNCs	Paclitaxel	<10%	Threefold	^[8]
Polymeric NPs	Insulin	Degradation	7.7% AUC	^[9]
CS-NPs	Insulin	Degradation	15.1 ± 0.9% bioavailibity	^[10]
PLGA-NPs	Doxorubicin	Low	363% bioavailibitiy	^[11]
NPs	Cefuroxime axetil	<50% and variable	Twofold	^[12]
PEG-coated liposomes	Human EGF	1–5%	2.5-fold	^[13]
Liposomes	N3-O-toluyl-Fluorouacil	39%	Four- to 6.6-fold	^[14]
Liposome	Cefotaxime	Low	2.7 to 2.3-fold	^[15]
Uncoated and acid folic coated-Liposomes	Vancomycin	<2%	3.9 to 12.5-fold	^[16]
Double Liposomes	Salmon calcitonin	Low	Six- to eight-fold	^[17]
Polymeric micelles	Genistein	Low	Threefold	^[18]
Polymeric micelles	Fenofibrate	Approximately 30%	1.5 to sixfold	^[19]
PAMAM dendrimers	Doxorubicin	Low	>300-fold	^[20]

CS: Chitosan; LNC: Lipid nanocapsule; NP: Nanoparticle; PAMAM: poly(amidoamine); PEG: Polyethyleneglycol; SLN: Solid lipid nanoparticle.

Table 2. *In vitro* model of gastrointestinal fluid described in the literature.
Gastric fluid	Composition	Ref.
SGF USP	pH of 1.2; pepsin	^[29]
SGF modified	pH of 1.2; pepsin and sodium lauryl sulphate or Triton®	^[30]
FaSSGF	pH of 1.6; pepsin, bile salt and lecithin	^[31]
Ensure® plus and full-fat milk	pH of 6.5; stimulate fed stomach: fat	^[32]
*Intestinal fluid*
SIF USP	pH of 6.8; pancreatin	^[29]
FaSSIF	pH of 6.5; 3 mM of bile salt and 0.75 mM of lecithin	^[26,30]
FeSSIF	pH of 5, bile salt; 15 mM of bile salt and 3.75 mM of lecithin
FaSSIF-V2	pH of 6.5; 3 mM of bile salt and 0.2 mM of lecithin	^[32–36]
FeSSIF-V2	pH 5.8; 10 mM of bile salt; 2 mM of lecithin and lipid digestion product and optionally pancreatin
Dynamic lipolysis model	pH of 6.5; various concentrations of bile salt, Ca²⁺ and lipase activity	^[37,38]
Lipase/colipase solution	pH of 7.4, lipase and colipase	^[39,40]

FaSSGF: Fasted state simulated gastric fluid; FaSSIF: Fasted state simulated intestinal fluid; FeSSIF: Fed state simulated intestinal fluid; SGF: Simulated gastric fluid; SIF: Simulated intestinal fluid; USP: United state pharmacopeia.

Table 3. The transport of nanocarriers across the intestinal barrier.
Formulation	Size and ζ potential if available	Model	Paracellular transport	Transcellular/uptake by enterocytes	Transcellular/uptake by M-cells	Ref.
PLGA-NPs	95 ± 20 nm	Caco-2 cells	No TEER decrease	NP uptake but low	NS	^[73]
PLGA-NPs	300–600 nm	Caco-2 cells	NS	Uptake caused by a collision-induced process: diffusion of marker	NS	^[74]
PLGA-NPs++	168 ± 20 nm; −10.4 ± 2.8 mV	Caco-2 cells	NSw	Uptake and localization in cytoplasm and in nuclei	NS	^[75]
PS-NPs	108 ± 2 nm; −48.8 ± 1.6 mV			Uptake and localization in cytoplasm
NPs	NS	Caco-2 cells	No TEER decrease	Passive transepithelial transport and energy-dependent uptake	NS	^[76]
CS NPs	433 ± 28 nm; +27.2 ± 0.8 mV	Caco-2 cells	TEER decrease	Internalization by adsorptive endocytosis, an energy-dependent, saturable process: including clathrin-mediated endocytosis, not including caveolae-mediated endocytosis	NS	^[77]
CS-coated PLGA-NPs TMC-coated PLGA-NPs	104.1 ± 1.2 nm; 36.2 ± 2.5 mV 106 ± 2.3 nm; 32.3 ± 2.1 mV	Caco-2 cells	Both open TJ and NPs adhere and release by paracellular drug transport	NS	NS	^[78]
CS-PGA NPs	140.2 ± 4.8 nm; 12.2 ± 0.6 mV 145.1 ± 3.7 nm; 13.2 ± 0.4 mV	Caco-2 cells	Ability to open the TJ	NS	NS	^[79]
CS nanocapsules CS-coated lipid NPs	266.6 ± 7.6 nm; −34.8 ± 0.6 mV 537 ± 16 nm; +29.2 ± 6.2 mV	Caco-2 cells	TEER decrease	Uptake by an energy-dependent process	NS	^[80]
multi-ion-crosslinked NPs	264.3 ± 4.5 nm, 28.5 ± 1.5 mV 254.2 ± 2.3 nm 9.2 ± 0.3 mV 270.7 ± 4.8 nm 4.9 ± 0.5 mV	Caco-2 cells	TEER decrease: NPs disintegrate: paracellular drug transport	NS	NS	^[81]
CS-PLGA NPs	290 ± 7 nm; +17.5 ± 3.6 mV	Caco-2 and HT29-MTX clone E12 cells	No TEER decrease	Transcytosis mechanism (active transport): adsorptive endocytosis and exocytosis release	NS	^[70,82]
PLGA-SMP	120 ± 1.0 nm; −39.2 ± 0.23 mV	Caco-2 cells	NS	No cytoadhesion	NS	^[83]
HAS-coated PLGA-SMP	124 ± 1.2 nm; −30.7 ± 0.75 mV			No cytoadhesion
WGA-coated PLGA-SMP	159 ± 1.2 nm; −33.9 ± 1.03 mV			Cytoadhesion (specific binding to membrane-associated glycoprotein by lectin–carbohydrate interactions) + internalization by energy-dependent transport
WGA-grafted PLGA nanospheres	570–1020 nm diameter	Caco-2 cells	NS	Cytoadhesion and cytoinvasion of particles. Energy-dependent uptake by the EGF receptor-mediated endocytosis pathway.	NS	^[84,85]
WGA-conjugated PEG-PLA NPs	95.3 ± 41 nm; −22.67 ± 1.21 mV	Caco-2 cells	NS	Rapid uptake Endocytosis via both clathrin- and caveolae-dependent pathways. After endosome creation transport occurs to both trans-golgi and lysosomes	NS	^[86]
PLA-TPGS NPS	343 ± 19 nm	Caco-2 cells	NS	Uptake	NS	^[87]
amino-CLIO NPs	21 ± 6 nm; 20 ± 5 nm; 18 ± 7 nm;	Caco-2 cells	No TEER decrease	Energy dependent endocytic mechanism	NS	^[88]
TMC-NPs	304 ± 6 nm; +14.9 ± 0.5 mV	Caco-2 cells	TEER decrease: open TJ, no difference between formulation	Alginate-modified TMC NPs increased drug transport through transcellular pathway in comparison with TMC NPs	NS	^[89]
Alginate modified TMS NPs	181 ± 14 nm; +6.0 ± 0.3 mV
PEI-NPs	200 ± 300 nm	Caco-2 cells	TEER decrease: erosion of particles and drug absorption	NS	NS	^[90]
SLNs	155.3 ± 22.1 nm; −32.23 ± 1.05 mV	In situ perfusion method in rats	NS	Passive transfer by diffusion across the lipid membranes		^[5]
LNC	26.3 ± 2.7 to 132.7 ± 5.5	Caco-2 cells	No TEER decrease	Clathrin- and caveolae-dependent endocytosis	NS	^[91]
Cyclodextrine	NS	Caco-2 cells	No TEER decrease	Cyclodextrin bound to cells surface and encapsulated drug transport by transcellular diffusion via lipophilic domains	NS	^[92]
Liposomes	70–100 nm			No uptake and no transport
mmePEG750P(CL-co-TMC) polymeric micelles	24.15 nm; −2.7 mV	Caco-2 cells and in FAE models	No paracellular transport	Passive diffusion of free drug fraction and free polymer Fluid phase endocytosis of polymeric micelles for translocation (no clathrine or caveolae endocytosis pathways)	No transport	^[93]
(PEG2000-DSPE) micelles	6 nm	Caco-2 cells, everted rat intestine	Decrease of TEER = Open TJ, improved paracellular transport	Good bioadhesion	NS	^[94]
Pluronic® F127 micelles	30 nm		No decrease of TEER
Pluronic P85 micelles	NS	BBMEC and Caco-2 cells	No paracellular permeability	Transcellular uptake via fluid-phase endocytosis	NS	^[95]
G3, G2 PAMAM dendrimers	NS	Caco-2 cells	Decrease of TEER: paracellular transport	Transcellular transport: energy-dependent process such as adsorptive endocytosis : clathrin-dependent endocytosis mechanism and rapid trafficking to endosomal and lysosomal compartments	NS	^[96–99]

BSA: Albumin; CS: Chitosan; DSPE: Distearylphophoethanolamine; HAS: Human serum albumin; mmePEG750P(CL-co-TMC): Monomethylether poly(ethyleneglycol)750-poly(-caprolactone-co-trimethylene carbonate); NP: Nanoparticle; NS: Not studied; PAMAM: Polyamidoamine; PEI: Poly-(ethylenimines); PGA: Poly(-glutamic acid); PLA: Poly(lactide);
PLGA: Poly(D,L-lactide-co-glycolide acid); PS: Polystyrene; SLN: Solid lipid nanoparticl; SMP: Submicroparticles; TEER: Transepithelial resistance; TJ: Tight junction; TMC: N-trimethyl chitosan; TPGS: Vitamin E TPGS; WGA: wheat germ agglutin.

Box 1. Examples of nanocarriers transported by M-cells.
Nanocarrier	Ref.
• PLGA nanoparticles anchored with Ulex europaeus agglutinin 1 ligand (UEA-1)	^[129]
• PEGylated PLGA- nanoparticles grafted with RGD peptides	^[130]
• PEGylated PLA:PLGA nanoparticles	^[59]
• RGD-coated polystyrene nanoparticles	^[131,132]
• UEA-1-labeled liposomes	^[133]
• poly(isobutylcyanoacrylate) nanocapsules	^[134]
• Polyalkylcyanoacrylate nanocapsules	^[135]

Sidebar

Executive Summary

Drug encapsulation in nanocarriers can lead to a significant improvement of its bioavailability. After being administered via oral route, the fate of nanocarriers is determined by their interaction with the physiological environment.

Chemical interactions with the gastrointestinal tract

The main factors to consider are chemical stress (i.e., pH, enzyme), residence time and volume of fluids.
Some modification of the nanocarrier formulation have been implemented with success to enhance their stabilities.
Biorelevant media have been used to study the stability of nanocarriers in vitro, but they do not really mimic physiological conditions for this purpose.

Diffusion across intestinal epithelium

Prior to intestinal absorption nanocarriers must diffuse across mucus. Their electrical charge and polarity can be adapted to facilitate this diffusion process.
Different mechanisms can be used by nanocarriers to cross the intestinal barrier: transcellular transport (M-cells or enterocytes) or paracellular transport, which remain limited, but can be favoured by nanocarrier components.
Three types of endocytosis mechanisms can be used by nanocarriers for their transport across enterocytes: clathrin-mediated endocytosis, caveolae-mediated endocytosis and caveolae- and clathrin-independent endocytosis.
The factors helping nanocarriers to use one pathway or another have yet not been fully elucidated. The size of the nanocarrier is often claimed to play a role in its transport mechanisms.

Properties of nanocarriers governing their fate in the absorption process

The size and nature of the polymer components, surface charge and moieties are key parameters to determine the fate of nanocarriers in the absorption process.
These key parameters can be optimised by modifying the formulation or the production process (examples are given for lipid nanocapsules, liposomes and polymer nanoparticles).

Concluding remarks

Nanocarriers can be designed to optimise the bioavailability of the encapsulated drugs. The knowledge of the relationship between their physicochemical nature and the gastrointestinal physiology is mandatory to reach this goal.
Besides the bioavailability issue, it is also possible and interesting to design nanocarriers of new generation, being able to be absorbed while keeping their integrity, and thus being able to behave as targeting nanovectors, as injected via intravenous route.

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Biopharmaceutical Parameters to Consider in Order to Alter the Fate of Nanocarriers after Oral Delivery

Conclusion & Future Perspective

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