Chemistry for Medicine 1
医用化学１(1st period, Friday)
November 9th, 2018
Why size matters? ~ From the anatomic viewpoint (continued)- Interaction of particles and biointerface~For control of cellular uptake~-Akihiro Kishimura(Associate Professor,
Katayama Laboratory)
kishimura.akihiro.776@m.kyushu-u.ac.jp

Introduction to Drug Delivery System(from the engineering viewpoint)5

Nov 2ndWhy size matters? ~ From the anatomic viewpoint(人体の構造とサイズ感)6

Nov 9thInteraction of particles and biointerface ~ For control
of cellular uptake (微粒子のバイオ界面との相互作用)7

Nov 16th

Introduction to pharmacokinetics andpharmacodynamics (PK/PD入門)

8

Nov 22th

Formulation design based on nanotechnology (ナノ剤形の設計と疾患治療)

Teaching material：Open access on BookRoll（e-learning system）
教材 - 教材一覧 - Others - 公開資料（岸村顕広）(Contents - List Contents - Others - 公開資料（岸村顕広）)

Blood Filtration by Kidney
糸球体がボウマン嚢に包まれたものを腎小体という。

“Nephron” plays a main role ofkidney function.

Renal
lobe

遠位
尿細管 Nephron

CortexGlomerulus

Renalpyramid

Renal
corpuscle

MedullaRenalpyramid

Tubularreabsorption

collectingductRenal corpuscle・Glomerulus

4

Tubular reabsorption
From renalarteryTo renalvein

Glomerular
capillary(fenestrated)

Endothelial
cells

Podocyte

Mesangium

Podocyte

Urine

Glomerular
capillarylumen

Bowman’s
capsuleGlomerular
capillarylumen

Filtration
Glomerular
capillary(replica; EM image)

Urine

Urine

Glomerularbasement
membraneFiltration apparatus: Three-layered structure
Fenestration of glomerular capillary
Podocyte
Basement membrane

Fenestration

Endothelium fenestration: 50-100 nm, thickglycocalyx layer repel blood cells.
Basement membrane: Network layer of type-IV
collagen; 240-370 nm thick. It contains heparinsulfate with high content, and shows negative
charge.
→ Blocking passage of serum albumin andnegatively-charged solutes.
Slit diaphragm: allows passage of substances< 4-6 nm. Glycocalyx gives negative charges.
Foot process of
podocyte
Slitdiaphragm

Charge-selective &size-selective barrier

Basement membrane

Endothelial cells
Glomerular capillary lumen

Schematic illustration of glomerular ﬁltration apparatus

Urine
Glycocalix
Footprocess of
podocyte

Basement membrane

TypeIV collagen

Endothelial cells

Capillary lumen

Plasmaprotein6

acromolecular polyrived from smooth muscle cells and possess phagocytic properties to
onstrated to trigger
keep the GBM ﬁlter free of debris, as well as secretory functions solinding lectin pathway
cited in case of glomerular injuries [87].
DCs integrating thesemplications of such
For globular
proteins,
4.2. Glomerular
ﬁltration hydrodynamic size < 5-6 nm can be
ed to minimize compassed through. (MW ~ 60,000)
for vaccination purConvective and diffusive forces in the glomerulus capillaries compel
Forpolymers,
arelistedin Table1 the Bowman's
which potentiate
the ﬁltration ofresults
blood solutes
fromthe capillary
lumen toploited to maximize
Quantum< 5.5
nm
can bepassedthrough.
capsule.dots
Structuresof theglomerulus
exert
qualitativeand quantitative

Size-selectivity✓✓✓
controlof
on somewhat is ﬁltered.
Proteins
with hydrodynamic(D )carbonnanotubes
werediameters
confirmed.
✓ Passage
smaller than 5 to 6 nm are freely ﬁltered by the glomerulus, while larger
large
particles
werereported
toequivalentbe passed.
✓ Somesolutes
aregelretained.
For globular
proteins,
this size is
to ainteract with✓
CDCs.
Transportation by transcytosis from capillary side to urine

particulate CDCs enside?
ts with complement
urface epitopes or adough immunoglobusecretion is usuallyrallel, other constitue protein) could playcolloids through reed complement actiacid) (PEG-PDLLA)d β-globulins) or cellles and facilitate theearly kinetic, qualitan interactions shouldrotein adsorption on

H

Table 1
The glomerular ﬁltration cut-offs of different polymers.
PolymerCut-off(kDa)

Charge at
pH 7.4

Biodegradable

Ref.

Pullulan
DextranLinear PEG
PVA
PNIPAM*
PHPMA
Gelatin (alkaline-type, Ip 5.1)

~ 29
~ 29
30
30
32
45
55

0
0
0
0
–
0
–

Yes
Yes
No
No
No
No
Yes

[98]
[98]
[99]
[100]
[23]
[91]
[101]

PEG: poly(ethylene glycol) PVA: poly(vinyl alcohol) PNIPAM: poly(N-isopropylacrylamide)
PHPMA: poly(N-(2-hydroxypropyl)methacrylamide).
*Copolymerized with 5 mol% methacrylic acid to ensure solubility at 37 °C.

The journey of a drug-carrier in the body: An anatomo-physiological perspective.
Nicolas Bertrand, Jean-Christophe Leroux, Journal of Controlled Release 161 (2012) 152–163.

Capture by the Liver8

N. Bertrand, J.-C. Leroux / Journal of Controlled Release 161 (2012) 152–163
Capillary-richorgan; Retention of large amount of blood（~1/4）

nd 60 kDa. The molecular weight limit can beproteins [88]. Grafting polymer chains to drugs
od of circumventing renal ﬁltration and increas89]. Still, today, PEG remains the most frequently
gment the DH of therapeutic molecules [70,90],
polymers [91–93] as well as synthetic linear
ve also been employed for this purpose. Several
non-PEG polymers are currently in preclinicalnt stages. The excretion limits of different macted in Table 1. Macromolecules with sizes situatthreshold, must distort and reptate through the
Front side such
ered. Factors affecting their deformability,
as well as intra-Galland intermoleculararchitecbladdernﬂuence their glomerular ﬁltration [23,96,97].
DCs are toolarge toof
belungﬁlteredwithout
prior
Replicablood
vesseltions include quantum dots, shown to be ﬁlp to 5.5 nm [102,103], and carbon nanotubes
shape of carbon nanotubes might promote
by favourable orientation in the blood ﬂow
ve transcellular transport mechanisms [108].
l studies are still needed to conﬁrm that theiriently fast to prevent accumulation and toxicext. Recently, an interesting study has shown
gium could be targeted by particulate CDCs
~75 nm [109]. Compared to similar particles
zes, colloids of this diameter are small enoughhelial fenestrae and sufﬁciently large to inter-To the heart & pulmonary circulation

The liver engages in numerous metabolic,immunological and endocrine functions. It
receives blood from the gut and the heart via
the portal vein and hepatic artery, respectively.
Blood circulates through a permeable
discontinuous capillary network, (thesinusoids) to reach the central and hepaticveins.

Hepatic lobules
Hexagonal architecture with 0.5-2 mm wide
Hepatic cell plate

endothelial cell
Centralvein

Kupffer cell

Sinusoid
毛細胆管Space of Disse

Sinusoid

To hepaticvein &
inferior vena
cava

From hepatic
artery &portal vein
hepatic
cells

小葉間胆管
小葉間動脈
小葉間門脈

小葉間動脈

小葉間胆管

類洞
Sinusoid✓ Sinusoid: 5 to 10 μm-wide blood vessels having a fenestrated epithelium
without any basal membrane- The gap between endothelial cells: 30-500 nm- Size of fenestration: 100–150 nm

Sinusoid & endothelial cells

10

Pores

Kupffer cell (yellow)

Space ofDisse
hepatic cells

Endothelial cell (pink)
Sinusoid

hepatic cells (orange)

Sieve plate (cluster of fenestra5on)

Kupﬀer cells- Macrophages residing in liver.

(80-90% of macrophage in the body is
Kupﬀer cells.)- Phagocytosis occurs aEer the mul5valentcontacts of the colloid with themacrophage and spreading of the cell
membrane around the par5cle to engulf it.

Kupffer cell

Liver cell

Liver
Spleen/lymph node
CNS
Kupffer cell

Lung
Peritoneal

cavityConnective tissueBone『免疫学コア講義』(南山堂)Hepatic plasma flow rate

Smallermacromolecules

Glomerular filtration rate

Liver uptake clearance (mL/h)

Positively
chargedmacromol.

InulinMacromol. with slightnegative charge

Rate of fluid endocytosis

Urinary excretion clearance (mL/h)
12

Inulin: MW~5,000 (polysaccharide). Completely excreted from kidney.
Standard substance for renal clearance measurement.

account when targeting this pathway. Similarly, the upper size thresholdfor the internalization of colloids via AGPR seems to be situated below
90 nm [157]. This limits the type of CDC which can be delivered throughA lymphaticorgan; filtration of old RBC and foreign
this route.
materials& approach
pathogens.
Anotherconsists of decorating CDCs with hepatocyteArteryopen intargeting lipoproteins either
before administration
or inissitu,
Splenic
red pulp [53,55]
after injection[52,158]. AlthoughSinusoid
cord effective targeting to hepatocytes
splenic cord
can be achieved, the ubiquitous nature of lipoprotein receptors in different tissues can lead to non-speciﬁc distribution and subsequentside-effects [48]. Finally, because non-parenchymal liver cells also
possess physiological and pathological functions, their targetingcanSievingby rodsometimes be desirable. Scavenging receptors can serve to target
cell slit.
Kupffer and endothelial cells [158,159], while coupling vitamin A on
the surface of CDCs revealed an effective way of delivering actives tostellate (Ito) cells that play a fundamental role in liver ﬁbrosis [160].

Sieving through the Spleen

splenic
cord

5.4. Biliary excretion

CentralSplenic
Macrophage
Bile is composed of water, bile acids, cholesterol, phospholipids,
arteryand proteins. Hepatocytes regulate passage from the space of Disse
sinusoid
white
to the bile canaliculi (Fig. 4). Various active transporters are responlooks like apulp
sible for the excretion of small molecules [161] while para- and transSinusoid “slit” of rod
cellular transport is available for high molecular weight compounds[162]. Vesicular-dependent transcytosis occurs either through ﬂuidcells.
Plateletphase or receptor-mediated endocytosis (Fig. 4). The latter pathway either transits to catabolic lysosomes (e.g., AGPR) [163,164] or not (e.g.,
SievedRBC
polymeric IgAs) [162]. Biliary excretion
is
the
only
excretion
pathSplenic
Fig. 5. Structure of the spleen. A. The spleen parenchyma is protected by a ﬁ
way available for non-biodegradable
CDCs with DH larger than 6 nm.
vein
and is composed of the white and red pulps. B. From the trabecular circulatio
Unless they possess chemical moieties that can be recognized byempty into the splenic sinusoids (closed circulation) or directly into thehepatocytes, soluble CDCs must undergo ﬂuid-phase endocytosis to→ Fresh & soft RBCs can pass the sieve,(open circulation). C. Reticular ﬁbres confer a highly-tortuous architectu
transit toward the bile canaliculi [164]. Experiments on isolated perpulp, and blood components must squeeze through the 200-nm wide fene
but old
RBCs
arerigid &of macromolefused&
ratrigid
livers have
shown
thattrapped;
the biliary excretion
sinusoids. The white squares delimit zones zoomed in the following panel.
Rat; SEM(PEG,nm)dextran,inulin andare
proteins)
to be independent
largecules(> 200materials
alsoseems
trappedWBC
image
Rod cellof molecular weight, from 2 to 500 kDa [163,165]. Cationic and anion(endothelilacell) Anatomically, the spleen is coand engulfedmaturation
and recycling.
ic charges onby
themacrophages.
solutes promote and hinder excretion, respectively
細網細胞

Summary of size v.s. systemic circulation
Please remember surface charge, rigidity, and shape etc. areimportant factors as well as size.
Lung capillary>10 µm10µm

splenic
Sinusoid> 200 nm

1
µm

Liver
fenestrae>150 nmCell-cell gap ofcontinuous capillary>20 nmGlomerular
filtration
>5 nm

10
nm

100
nm

1
nm

Oligo DNA/RNAMicrosphere(~4 nm)IgG(~5 nm)Liposomes(50-200 nm)

Nanomedicine

Polymericcapsules(20-200 nm)

Serum
Albumin

Organic
compounds(M.W. ~500)(~4 nm)15

Lymphatic vessel- Lymphatic vessels are found in the vicinity of vein; distributed over the body
except epithelium tissue, eyes, central nerve system, spleen. Flow is driven bymuscle contract or motion of the body. It goes back to the vein at thoracic duct;
but flow rate is very slow (1-2 L/day).
- It conveys some compounds, pathogens, dead cells, cancer cells, immune cells(particularly, dendritic cells).
- One end is closed.
- Interstitial fluid is absorbed by lymphatic vesseles.

Many large
gaps

Thoracic
duct

Valve

16

DDS based on drug carriers (Review)
Design should be performed considering 1.‒3.
Molecular carrier- Low Molecular weight (MW)- Macromolecuels{

Natural: Serum albumin, polysaccharide
Synthetic: Polyethylen glycol (PEG)(PEG; stealth property.)Par5culate carrier- Low MW components:

Liposomes (cell-membrane mimic),
Emulsions, Lipid microspheres- Macromolecular components: Microspheres,

Nano-capsules (micelles, vesicles),Nano-gels

Bio-based carrier
Red blood cells, antibody, viruses, proteins, etc..

17

EPR effect: A typical example of passive targeting
In tumor 5ssue and inﬂammatory 5ssue, permeability of capillary is enhanced,
but reten5on of larger substances is found due to dysfunc5on of lympha5c drainage.
For the cancer treatment...
Long-circulation
Nano-carriers

Tumor
TissueSize is a critical factor!!
EPR (Enhanced Permeability andRetention) effect: Size < 100–200 nm

<12µm

Lung
uptakeNormaltissueLiveruptakeImmature Lymph

Higher drainage
Lowerdrainage

Blood
Stream
RES uptake

KidneySize:
200 nm~3 µm

M.W. < 30,000

Normal lymph: Drug: Nano-medicine

Leaky
Blood Vessel

Tumor tissue

Effectively found for “stealth” particles.

Y. Anraku, et al., JACS, 2010, 132, 1631.

Preparation of Nano-PICsomes
PEG(45)-PAsp(75)
O
MeO

O

m

N
H

fPEG ~ 8%

+
O
N
H

H
N

H
N
o O
O–
O
Na+

H
N

H
N

NanoPICsome

H
p'

O
O

R=

n

Na+

H
N

O
NH

p
O–

O

o'

R

H

10 mM PB
with 0 mM NaCl
(pH 7.4)

NHnR

Homo-P(Asp-AP) (82)

NH3
Cl–

1 mg/mLTEM

Cryo-TEM

DLS

100 nmSize: ~100 nm
Thickness: <15 nm

100 nmCollaborated with Terabase Inc.

Unilamellar Structure

Y. Anraku, et al., Chem Commun, 2011, 47, 6054.

Plasma Clearnace of
CL-PICsome in mice
CL-Cy5-PICsomes(100 nm)PEG-P(Asp)-Cy5

Cy5-PICsome w/o CL

100 nm-Polymersome

PEG-poly(ethylethylene)(40-37)●: 35.3 nm (micelles)●: 102 nm●: 158 nm●: 197 nm●: 256 nm●: 298 nm

Plasma Clearance (%)

Plasma Clearance (%)

Plasma Clearance

38.0

Mean
Residence
Time (h)
36.2

102

51.2

158

69.2

197

71

256

47.3

298

45

Size (nm)τ1/2 = 16–28

D. E. Discher et. al. J. Control. Release 2003, 90, 323.

Drug distribution at the target tissue (Review)After delivery to the target tissue, infiltration to the tissue &internalization into the cells is sometimes required.
CapillaryPlasma protein

Drug

Blood cells

Blood flow

Endothelial cells

Tissue space

Tissue cells

21

Typical structure of Biomembrane
Extracellular space

Glycochain

Cholesterol

Lipidbilayer

Intracellular space Membrane proteins

Pflugers Arch - Eur J Physiol (2007) 454:345–359

S. Reitsma, et al.,Eur. J. Physiol. 454 (2007) 345–359.

Cells are oEen coated by glycocalyx(糖衣), a ﬁbrous meshwork ofcarbohydrates (glycoproteins,
glycolipids, proteoglycans, andpolysaccharides). Par5cularly, it isfound for epithelial cells (上皮細胞) and endothelial cells (内皮細胞), characteris5cally as a thicklayer. => Regula5on of the vascularpermeability, modula5on of theinterac5ons between blood andendothelial cells, andtransmiRance of physical forces tothe cytoskeleton of endothelial
cells.

22

Type

Carrier

Energya. Passive transport
1) Simple diffusion

Transport across the membrane
Hydrophobic
compoundi) DissolutionNoNo
diffusionii) RestrictedNoNo
diffusion
By pore or(filtration)intercellular gapiii) Solvent
drag

No

No

Need

No

Passive transportb. Active transport
1) Primary active
transport

Need

Need
Na+, K+, H+

Pump, ATPase2) Secondary active transporti) Symport

Need

Need

ii) Antiport

Need

Need

iii) Uniiport

Need

Need

Chargedcompound

The thermodynamic process driven byconcentra5on gradient, and/or electrochemical
gradient (down-hill transport). It involves noenergy consump5on; but it is dependent on thepoten5al.
1-i): Only for hydrophobic small compounds, andgasses.
Facillitated transport: Protein channels or carriers
are required.

By pore orintercellular gap

2) Facilitateddiffusion

Active transport

etc…

Energy-dependent process. Up-hill transport.
Speciﬁc protein carries/transporters are
required.
Primary: Directly utilizes ATP, GTP.
Secondary: The up-hill transport coupledwith the down-hill transport using
concentration gradient produced byprimary active transports (Na+, H+ gradient,etc..) (Symport, antiport). Uniport: Driven bymembrane potential created by primaryactive transports.

Simple diﬀusion & Fickʼs law
Many of low molecular weight drug showhydrophobic property. Therefore, simple
diffusion process is important; but it is amain reason of whole-body distribution ofdrugs.
- It only follows thermodynamic principle;
influence from similar structure compoundis limited.
- Flux of transport is not significantly
dependent on temperature.
-

Intracellular
space

Extracellular
space

Water Flux Jv
Permea+on
coeﬃcient Pm

Concentra+on
outside of cell

Cout

Solvent drag(1–σ)C·Jv

Reﬂec+on
coeﬃcient σ
Surface areaA

Diﬀusioncoeﬃcient Dm

Restricted diffusion, Solvent drag: Protein channel
or carrier, or intracellular gap is required.
Solvent drag: Transport of solvent involves drugtransport.
Cin Concentra+on inside of cell

Concentra5on
outside of cell

Thickness L

J = DmA(Coutm–Cinm)/L
K = Coutm/Cout = Cinm/Cin=> J = DmKA(Cout–Cin)/L= PmA(Cout–Cin)

https://www.youtube.com/embed/FZccM0B5PrE

Examples of facilitated transport
https://biologydictionary.net/facilitated-diffusion/

Examples: Aquaporin (for water),glucose transporter, ion channels

https://www.youtube.com/embed/IX-kLh34KcQ
https://www.youtube.com/embed/FZccM0B5PrE

25

Cellular uptake and transportation by vesicles
Invagination or budding of cell membrane results in formation of vesicles.

Endocytosis

1. Contact to cell surface
2. Vesicle formation &granule release
3. Transportation

I. Canton, G. Battaglia,
Chem. Soc. Rev. 41 (2012) 2718–2739.

→ After endocytosis, materials may escape from endosome to cytosol, if needed.

Cathrin-mediated endocytosis
Firstly, materialinteract withsome receptors. clathrin
Triskelion forms “a coated pit”.

Upper limit fore f fi c i e n t
endocytois is~120 nm. But,
some cells
internalize larger
paricles (< 300nm).

Caveolae-mediated endocytosis
An invaginated pit with 50-80 nm in size ﬁnally allows forendosome formation.
Lipid raE (the plasma membranes of cells contain combina5ons ofglycosphingolipids and protein receptors organized in glycolipoprotein
microdomains) forms a ﬂask-shaped invagina5on with help of caveolin.

28

Other types of endocytosis
RhoA-mediated
細胞内骨格であるアクチンの制御に関わるRhoAの関与する経路。詳細は明らかでない部分が多いが、ある種のサイトカイン受容体の内在化に関連する。アクチンはエンドサ
イトーシスの機構に関わる重要な因子であるので、関連性は深いと思われる。

CDC42(cell division cycle42)-mediated
幅は< 50 nmチューブ状200-600 nm（長さ）に陥入する。
CDC42は、細胞の成長、分化、アポトーシスなどに関与し、アクチンや細胞ストレスの制御因子であるため、関係が深いものと思われる。GTP結合性。

ARF6-mediated
こちらもチューブ状に陥入する。発見から日が浅く、詳細は不明。ARF6は膜の曲率制御に関連があるとも言われる。（GTPと結合して曲率が上がり、くびれる。）

Flotilin-mediated
カベオリンと類似のコンフォメーションを持つタンパク質であるが、カベオラ型とは独立してエンドサイトーシスを起こすらしい。
29

Macropinocytosis
Engulfment of a large quantity of external fluid by the formation ofwaving sheet-like extensions of the plasma membrane that close,
thus forming large(> 200 nm)
organelles called
macropinosomes. Polymerization of actin is a key step for
engulfment.
Lamellipodia- Circularlike
ruffle(葉状仮足様)Bleb
Lamellipodialike

CircularruffleBleb
Green: actin
filaments

30

Phagocytosis
Endocytosis performed by immune cells, e.g., macrophages, dendritic
cells, mast cells, neutrophils and so on. Rather large (~µm?).

For opsonized matreials(a) For IgG, recognition by Fcγ
receptor results in phagocytosis.

(b) For C3b, recognition by CR3(complement receptor 3) results inphagocytosis.

(c) Engulfment of opsonized RBC.
Actin filaments were labeled by FL
proteins.

???

???

32
M. Zhu, et al., Acc. Chem. Res. 46 (2013) 622–631. Fig. 3

particle weree coated withhad a homogeneous hydrophilic ligand shell, whereas 34-66 OT
and 66-34 OT particles had a hydrophilic–hydrophobic striatedSurface chemistry & cellular uptake- Usual cell surface is negatively charged due to glyco-chains and lipid
our particles used in thishead
study. group. => Cationic particles are favorable, but sometimes lead
Thermogravimetric⇣Potential §Ligand shell morphology/tohighcytotoxicity.
‡
analysis (%)(mV)
chemical structures- In in vivo conditions, cationic surface often induces adsorption ofproteins. (low biocompatibility）→ Suppression of non-speciﬁc uptake.
Biocompatible polymer
1538.0± 5.30 but, may
result in low cellular uptake.
HomogeneousO
Poly(ethylene“PEG
dillenma”
O Na
S
O
HS
glycol) (PEG)nO
PMPC
Poly(2-methyloxazoline) MUS
=

=

+

n

Poly(N-vinyl
pyrrolidone) (PVP)

N

N

n
O

O

n

O–

Unstructured

31.1± 0.73
structured

A. Verma and F. Stellacci

O

HS

=

randomOS

O – Na +=13
homogeneous

O

O

ace-

P

O
N+

O

O
MUS Poly(2-(methacryloyloxy)ethyl phosphorylcholine)HS

Surfacebr-OT structure

Structured

33.1± 0.64

O

=

15

HS

S

O – Na +=ynthetic
particleinteracrted theligands/
particleligandsurfacenaturaloup hasility ofd nanoze, zeta
y, and

–

MUS

O

OT

A. Verma, et al., Nat. Mater. 2008, 7, 588.

HS

to surface reconstruction

Surface of
the ARTICLE
particle
REVIEWATERIALS DOI: 10.1038/NMAT2442
Competitive binding
interactions dependon protein concentration
and body fluid composition

Characteristic
protein on/off
rates depend on
material type
and proteincharacteristics

Available surface
area, surface coverage
and angleHydrophilicof curvature
determineoradsorptionhydrophobic
profiles interactions

Crystallinity

Electronic
statesParticle
Surfacecomposition
ity
instabilHydrophobicity
wettability

wettability

Size

Charge (for example cationic binding)Chargeb

Steric hindrance
prevents binding+ + + + +
_

O.2

SH
SH

Protein conformationalchanges cause loss of
enzyme activity

e

S
S

–

_

O.2

e

S
S

Release of surface
free energy–

O2
Release of surface
free energye–h+Protein conformation,functional changes

Impact onproteinstructureand function

Proteinfibrillationh+Possible events after
Impact onproteinstructureand function

interaction withproteins.
Surface

Protein conformationalchanges cause loss of
enzyme activity

O2e–

Surfacereconstruction

Electron–holepairs leadto oxidative
damageSH
SH

Surfacereconstruction

Electron–holepairs leadto oxidative
damageSteric hindrance
prevents binding

A. E. Nel, et al., Nat. Mater. 2009, 8, 543-557.

Charge (for example cationic binding)

b

Size

HydroPossible events onparticle
surface.
phobicity
Chargee

Hydrophilicor hydrophobic
interactions

Particle
Surfacecomposition
y
it
il
b
insta

Protein binding
accelerates
dissolution ofsome materials

Available surface
area, surface coverage
and angle of curvature
determine adsorption
profilesCrystallinity

Electronic
statesBinding interactions releasesurface free energy, leading
to surface reconstruction–

Protein binding
accelerates
dissolution ofsome materialse–+ + + + +aCharacteristic
protein on/off
rates depend on
material type
and proteincharacteristics

Surface Protein conformation,
opsonization/functional changes
liganding allows
interaction
with additional
Protein nano–bio interfaces
fibrillation

Amyloid
fibre

Exposure
to cryptic
epitopes

Proteincrowding,
layering,
nucleation
Immunerecognition34

Eﬀect of Size on cellular uptake➡ Size-dependency of interaction between antibody-functionalized gold
nanoparticles (GNPs) and cells: Different internalization and signaling.
2 nm GNPs
40 nm GNPs
70 nm GNPs

Receptor

vesil
ce

核

重ね合わせ

10 nm

40 nm

W. Jiang et al. Nat.
Nanotechnol. 2008, 3, 145.
35

Eﬀect of shape on cellular uptake (1)Nano-/micro-hydrogels with various
sizes and shapes were prepared, andcellular uptake was examined.

20 µm

20 µm

dependent on the size and aspect ratios.

20 µm

20 µm

20 µm

20 µm

1 µm

1 µm

➡ Internalization into HeLa cells is

1 µm

1 µm

1 µm

J. M. DeSimone et al., PNAS, 2008, 105, 11613.

Eﬀect of shape on cellular uptake (2)Macrophages (RAW264.7)• Cervical cancer cells (HeLa)•- More ﬂat & bigger AuNP

showed higher cellular
uptake.
- Longer reten5on 5me on
the cell surface
eﬀec5vely contributes…?

K. Nambara, K. Niikura, et al.,Langmuir, 2016, 32, 12559.

Surface area/particle

Volume/particle

37

Transport from capillary
Molecular
weightLow
Molecular
WeightOrganic
chemistry

32

Oxygen180

Glucose3001,000

Low-molecularweight drug

70,00015 nm

Nano-scale 170,000
Objects
Polymer/colloid

O2

Albumin, etc

20-150 nm
tens–hundredsof nm

Viruses(Inﬂuenza, Ebola…)

7 μm

Type of transport-

Diffusion-

Protein carrier

Nano-physiology

Ig（抗体医薬）

Nanomedicine

sciences

血球

Substances

Size

Red Blood Cell-

Only leaking?
Exosome-

Bleeding