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Background Pulmonary route is an attractive target for both systemic and local drug delivery, with the advantages of a large surface area, rich blood supply, and absence of first-pass metabolism. Numerous polymeric micro/nanoparticles have been designed and studied for controlled and targeted drug delivery to the lung. Area covered Among the natural and synthetic polymers for polymeric particles, poly(lactic acid) (PLA) and poly(lactic-co-glycolic acid) (PLGA) have been widely used for the delivery of anti-cancer agents, anti-inflammatory drugs, vaccines, peptides, and proteins because of their highly biocompatible and biodegradable properties. This review focuses on the characteristics of PLA/PLGA particles as carriers of drugs for efficient delivery to the lung. Furthermore, the manufacturing techniques of the polymeric particles, and their applications for inhalation therapy were discussed. Expert opinion Compared to other carriers including liposomes, PLA/PLGA particles present a high structural integrity providing enhanced stability, higher drug loading, and prolonged drug release. Adequately designed and engineered polymeric particles can contribute to a desirable pulmonary drug delivery characterized by a sustained drug release, prolonged drug action, reduction in the therapeutic dose, and improved patient compliance.
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Journal of Pharmaceutical Investigation (2019) 49:427–442
https://doi.org/10.1007/s40005-019-00443-1
REVIEW
Poly(lactic acid)/poly(lactic‑co‑glycolic acid) particulate carriers
forpulmonary drug delivery
FakhrossadatEmami1· SeyedJamaleddinMostafaviYazdi2· DongHeeNa3
Received: 6 April 2019 / Accepted: 15 April 2019 / Published online: 22 April 2019
© The Author(s) 2019, corrected publication 2019
Abstract
Background Pulmonary route is an attractive target for both systemic and local drug delivery, with the advantages of a large
surface area, rich blood supply, and absence of first-pass metabolism. Numerous polymeric micro/nanoparticles have been
designed and studied for controlled and targeted drug delivery to the lung.
Area covered Among the natural and synthetic polymers for polymeric particles, poly(lactic acid) (PLA) and poly(lactic-
co-glycolic acid) (PLGA) have been widely used for the delivery of anti-cancer agents, anti-inflammatory drugs, vaccines,
peptides, and proteins because of their highly biocompatible and biodegradable properties. This review focuses on the char-
acteristics of PLA/PLGA particles as carriers of drugs for efficient delivery to the lung. Furthermore, the manufacturing
techniques of the polymeric particles, and their applications for inhalation therapy were discussed.
Expert opinion Compared to other carriers including liposomes, PLA/PLGA particles present a high structural integrity
providing enhanced stability, higher drug loading, and prolonged drug release. Adequately designed and engineered poly-
meric particles can contribute to a desirable pulmonary drug delivery characterized by a sustained drug release, prolonged
drug action, reduction in the therapeutic dose, and improved patient compliance.
Keywords Poly(lactic acid)· Poly(lactic-co-glycolic acid)· Microparticles· Nanoparticles· Pulmonary drug delivery
Introduction
Pulmonary drug delivery provides non-invasive method of
drug administration with several advantages over the other
administration routes. These advantages include large sur-
face area (100m2), thin (0.10.2mm) physical barriers for
absorption, rich vascularization to provide rapid absorption
into blood circulation, absence of extreme pH, avoidance of
first-pass metabolism with higher bioavailability, fast sys-
temic delivery from the alveolar region to lung, and less
metabolic activity compared to that in the other areas of
the body (Ali 2010; Lee etal. 2018; Yu etal. 2016). The
local delivery of drugs using inhalers has been a proper
choice for most pulmonary diseases (Pison etal. 2006),
including asthma (Basheti etal. 2017; Lavorini etal. 2008),
cystic fibrosis (Adi etal. 2010; Bilton etal. 2011), chronic
obstructive pulmonary disease (COPD) (Schulte etal. 2008;
Sulaiman etal. 2017), lung infections (Cipolla and Chan
2013; Golshahi etal. 2011; Oliveira etal. 2017), lung cancer
(Zhu etal. 2017), and pulmonary hypertension (Gupta etal.
2011; Kanwar etal. 2016). In addition to the local delivery
of drugs, inhalation can also be a good platform for the sys-
temic circulation of drugs (Moroz etal. 2016; Rytting etal.
2008; Thwala etal. 2017). The pulmonary route provides
a rapid onset of action even with doses lower than that for
oral administration, resulting in less side-effects because of
the increased surface area and rich blood vascularization
(Ali 2010).
After administration, drug distribution in the lung and
retention in the appropriate site of the lung is important to
achieve effective treatment (Labiris and Dolovich 2003a).
A drug formulation designed for systemic delivery needs to
be deposited in the lower parts of the lung to provide opti-
mal bioavailability (Poursina etal. 2016). However, for the
local delivery of antibiotics for the treatment of pulmonary
Online ISSN 2093-6214
Print ISSN 2093-5552
* Dong Hee Na
dhna@cau.ac.kr
1 Department ofPharmaceutics, College ofPharmacy, Tehran
University ofMedical Sciences, Tehran, Iran
2 Department ofMechanical Engineering, Kyungpook
National University, Daegu41566, RepublicofKorea
3 College ofPharmacy, Chung-Ang University, 84
Heukseok-ro, Dongjak-gu, Seoul06974, RepublicofKorea
428 F.Emami et al.
1 3
infection, prolonged drug retention in the lungs is required to
achieve proper efficacy. For the efficacy of aerosol medica-
tions, several factors including inhaler formulation, breath-
ing operation (inspiratory flow, inspired volume, and end-
inspiratory breath hold time), and physicochemical stability
of the drugs (dry powder, aqueous solution, or suspension
with or without propellants), along with particle characteris-
tics, should be considered (Labiris and Dolovich 2003a, b).
Microparticles (MPs) and nanoparticles (NPs), including
micelles (Mahajan and Mahajan 2016), liposomes (Bhardwaj
etal. 2016), solid lipid NPs (Ji etal. 2016), inorganic parti-
cles (Seydoux etal. 2016), and polymeric particles (Oliveira
etal. 2017) have been prepared and applied for sustained
and/or targeted drug delivery to the lung. Although MPs and
NPs were prepared by various natural or synthetic polymers,
poly(lactic acid) (PLA) and poly(lactic-co-glycolic acid)
(PLGA) particles have been preferably employed owing to
their biocompatibility and biodegradability (Kumari etal.
2010; Mohamed and van der Walle 2008; Na etal. 2007).
Polymeric particles retained in the lungs can provide high
drug concentration and prolonged drug residence time in
the lung with minimum drug exposure to the blood circula-
tion (Harush-Frenkel etal. 2010). This review focuses on
the characteristics of PLA/PLGA particles as carriers for
pulmonary drug delivery, their manufacturing techniques,
and their current applications for inhalation therapy.
Polymeric particles forpulmonary delivery
The preparation and engineering of polymeric carriers for
local (Tables1 and 2) or systemic delivery (Table3) of drugs
to the lung is an attractive subject. In order to provide the
proper therapeutic efficiency, drug deposition in the lung
as well as drug release are required, which are influenced
by the design of the carriers and the degradation rate of the
polymers (Ali 2010). Different varieties of natural polymers
including cyclodextrin, albumin, chitosan, gelatin, alginate,
and collagen or synthetic polymers including PLA, PLGA,
polyacrylates, and polyanhydrides are extensively used for
pulmonary applications (Abdelaziz etal. 2018). Natural pol-
ymers often show a relatively short duration of drug release,
whereas synthetic polymers are more effective in releasing
the drug in a sustained profile from days to several weeks
(Rytting etal. 2008). Synthetic hydrophobic polymers are
commonly applied in the manufacture of MPs and NPs for
the sustained release of inhalable drugs (Abdelaziz etal.
2018; Ungaro etal. 2012).
PLA/PLGA polymeric particles
PLA and PLGA are the most commonly used synthetic pol-
ymers for pharmaceutical applications (Campardelli etal.
2016; Panyam and Labhasetwar 2003). They are approved
materials for biomedical applications by the Food and Drug
Administration (FDA) and the European Medicine Agency
(Campardelli etal. 2016; Ernst etal. 2018). Their unique
biocompatibility and versatility make them an excellent
carrier of drugs in targeting different diseases (Ernst etal.
2018). The number of commercial products using PLGA or
PLA matrices for drug delivery system (DDS) is increasing,
and this trend is expected to continue for protein, peptide,
and oligonucleotide drugs (Mohamed and van der Walle
2008). In an invivo environment, the polyester backbone
structures of PLA and PLGA go through hydrolysis and
produce biocompatible ingredients (glycolic acid and lactic
acid) that are eliminated from the human body through the
citric acid cycle. The degradation products do not affect nor-
mal physiological function. Drug release from the PLGA or
PLA particles is controlled by diffusion of the drug through
the polymeric matrix and by the erosion of particles due
to polymer degradation (Anderson and Shive 1997). PLA/
PLGA particles often show a three-phase drug release profile
with an initial burst release, which is adjusted by passive dif-
fusion, followed by a lag phase, and finally a secondary burst
release pattern (Amatya etal. 2013; Rytting etal. 2008).
The degradation rate of PLA and PLGA is modulated by
pH, polymer composition (glycolic/lactic acid ratio), hydro-
philicity in the backbone, and average molecular weight;
hence, the release pattern of the drug could fluctuate from
weeks to months (Alexis 2005; Campardelli etal. 2016).
Encapsulation of drugs into PLA/PLGA particles afford a
sustained drug release for a long time ranging from 1week
to over a year, and furthermore, the particles protect the
labile drugs from degradation before and after administra-
tion (Hang etal. 2015). In PLGA MPs for the co-delivery of
isoniazid and rifampicin, free drugs were detectable invivo
up to 1day, whereas MPs showed a sustained drug release
of up to 3–6days (Dutt and Khuller 2001). By hardening
the PLGA MPs, a sustained release carrier system of up to
7weeks invitro and invivo could be achieved. This study
suggested that PLGA MPs showed a better therapeutic effi-
ciency in tuberculosis infection than that by the free drug.
Large porous microparticles
Inhalable PLA/PLGA MPs have been widely studied with
the aim to find strategies for the prolonged release of drugs
in the lung. The inhalable particles need to be small for
appropriate lung deposition, but this may result in low drug
encapsulation into MPs. The low drug content may require
frequent administrations to achieve maximal drug concen-
tration in the lung, which may cause the accumulation of
incompletely degraded polymers in the lung and subse-
quent adverse effects (Abdelaziz etal. 2018). Therefore,
429
Poly(lactic acid)/poly(lactic-co-glycolic acid) particulate carriers forpulmonary drug…
1 3
Table 1 Inhalable poly(lactic acid)/poly(lactic-co-glycolic acid) (PLA/PLGA) microparticles (MPs) for local delivery of drugs to the lung
Particles Drug Indication Preparation Tech-
nique
Excipients Particle properties
and outcome
References
Large porous PLA/
PLGA MPs
Montelukast Asthma Double emulsion-
evaporation
(w/o/w)
PEI-1 MMAD: 1.59
2.51μm
EE:75.789.3%
Patel etal. (2017a)
PLA MPs Rifampicin Pulmonary infection Electrospray PEC MMAD: 45µm
Sustained release
Priemel etal. (2018)
Large porous PLGA
MPs
Montelukast and
heparin
Asthma Double emulsion-
evaporation
PEI EE: 66.8% for mon-
telukast
Heparin adsorption
efficiency: 91.7%
Sustained drug
release
Patel etal. (2017b)
Homogenous PLGA
MPs
Rifampicin Tuberculosis Single emulsion-
evaporation (o/w)
with glass beads
PVA, PEI Particle size: 23µm
Sustained release at
7days
Liu etal. (2016)
Porous PLGA MPs Doxorubicin and
miR-519c
Lung cancer Double emulsion-
evaporation
(w/o/w)
Ammonium bicar-
bonate
MMAD < 10μm
Sustained release and
good anti-tumor
efficacy
Wu etal. (2016)
PLA/PLGA MPs 5-fluorouracil Lung cancer Spray drying Particle size:
1.21.5µm
Hitzman etal. (2006)
Large porous PLGA
MPs
Doxorubicin Metastatic lung
cancer
Double emulsion-
evaporation
(w/o/w)
PEMA, Ammonium
bicarbonate
Particle size:
14.1µm
MMAD: 3.6µm
Good phagocytosis
escapement
Retention for 14days
in mice lung
Kim etal. (2012)
Large porous PLGA
MPs
Doxorubicin and
TRAIL
Metastatic lung
cancer
Double emulsion-
evaporation
(w/o/w)
PEMA, Ammonium
bicarbonate
Particle size:
11.5µm
EE: 86.5% (doxo-
rubicin), 91.8%
(TRAIL)
Sustained release in
7days and reten-
tion for 7days in
mice lung
Proper anti-tumor
effect
Kim etal. (2013)
Large porous PLGA
MPs
Budesonide Asthma Double emulsion-
evaporation
(w/o/w)
PVA, Ammonium
bicarbonate
Particle size:
6.49.2µm
MMAD: 2.56.4µm
Density: 0.70.98g/
cm3
Pore size:
0.71.5µm
EE: 5676%
Oh etal. (2011)
PLGA MPs PGE1 Pulmonary arterial
hypertension
Double emulsion-
evaporation
PVA, PEI Particle size:
722µm
MMAD: 2.53.5µm
PDI: 1.55.2
Density: 0.10.45g/
cm3
FPF: 50.963.2%
EE: 61.299%
Bioavailability:
82-96%
Gupta and Ahsan
(2011)
PLA MPs Isoniazid and
Rifabutin
Tuberculosis Spray drying Particle size: 5µm
MMAD: 3.6µm
FPF: 78.9%
Yield > 60%
Muttil etal. (2007)
PLGA MPs Capreomycin Tuberculosis Solid in o/w solvent
diffusion-evapo-
ration and Spray
drying
Sodium oleate Particle size:
11.417µm
MMAD: 6.79.1µm
EE: 8990%
Schoubben etal.
(2010)
430 F.Emami et al.
1 3
good porosity of the MPs is a desired feature for inhalation
(Ungaro etal. 2006).
Large porous MPs (LPMs) demonstrate a sophisticated
formulation to improve deep lung localization and avoid
macrophage clearance (Fig.1). They are light particles with
ideal characteristics for pulmonary delivery, including large
geometric diameter (530μm), low density (< 0.4g/cm3),
and acceptable aerodynamic diameter (13μm) (Edwards
etal. 1998). The numerous pores in LPMs make them light
enough to ensure their deep lung deposition through inhala-
tion. However, MPs with geometric diameters < 5μm are
susceptible to aggregation through van der Waals force.
This causes some of the drugs to be retained in the device,
resulting in a lower yield of drug delivery to the lungs. In
addition, 13μm particles are phagocytosed by macrophage
clearance in the lung, thus, decreasing their activity (Patton
and Byron 2007; Ungaro etal. 2012). Alveolar macrophages
cannot capture large MPs with geometric diameters 20μm;
hence, there is a prolonged residence time in the lung. This
implies that light particles as well as large ones (530μm)
are highly desirable for drug delivery into deep lungs. Dif-
ferent types of porogens have potentials for the prepara-
tion of LPMs including extractable porogens (pluronics),
effervescent porogens (ammonium bicarbonate), osmo-
gens (cyclodextrins), and gas bubbles (hydrogen peroxide/
catalase) (Abdelaziz etal. 2018). Extractable porogens and
osmogens manifest the drawback of drug leakage through
pores because of aqueous channels formed within polymeric
microspheres. Effervescent porogens are preferred to mini-
mize drug loss and improve the encapsulation efficiency.
Kim etal. prepared doxorubicin-encapsulated large porous
PLGA MPs (DOX-LPM) by a water-in-oil-in-water (w/o/w)
double emulsion-evaporation technique using ammonium
bicarbonate as a gas-foaming porogen (Kim etal. 2012).
MMAD mass median aerodynamic diameter, ED emitted dose %, FPF fine particle fraction %, EE encapsulation efficiency %, PDI polydisper-
sity Index, PVP polyvinyl pyrrolidone, PVA polyvinyl alcohol, HPβCD hydroxypropyl-β-cyclodextrin, PEMA poly(ethylene-alt-maleic anhy-
dride), TRAIL tumor necrosis factor-related apoptosis inducing ligand; PGE1, prostaglandin E1, PEI polyethyleneimine; PEC polyethylene car-
bonate, PEG polyethylene glycol
Table 1 (continued)
Particles Drug Indication Preparation Tech-
nique
Excipients Particle properties
and outcome
References
Large porous PLGA
MPs
Doxorubicin and p53
gene
Lung cancer Double emulsion-
solvent evaporation
(w/o/w)
Ammonium bicar-
bonate
Particle size:
21.126.6μm
EE: 88.2% (doxo-
rubicin), 36.5%
(plasmid)
Enhanced invitro
anti-tumor and
apoptosis
Shi etal. (2014)
PLGA MPs PGE1 Pulmonary arterial
hypertension
Double emulsion-
evaporation
(w/o/w)
HPβCD, PVA Particle size:
8.514.5µm
MMAD: 0.75.5µm
Tapped density:
0.10.4g/cm3
PDI: 0.11.7
FPF: 3592%
Bioavailability:
6791%
Gupta etal. (2011)
PLGA MPs Rifapentine Tuberculosis Single emulsion-
evaporation (o/w)
and spray drying
PVA MMAD: 2.43.0μm
Span ~ 2
FPF: 5257%
ED: 8186%
Parumasivam etal.
(2016)
Large porous PLGA
MPs
Cinaciguat Pulmonary hyperten-
sion
Single emulsion-
evaporation (o/w)
PVA, PVP, Pluronic
F127
MMAD: 4.8-6.2μm
FPF: 19.836%
Retention > 36h
Sustained drug
release
Ni etal. (2017)
PLGA MPs Levofloxacin Cystic fibrosis Double emulsion-
evaporation
(w/o/w) with a
membrane homog-
enization
Lauric acid, PVA ED: 85.0%
FPF: 30.2%
MMAD: 7.1μm
Sustained-release:
75% in 72h
Gaspar etal. (2019)
Large porous PLGA
MPs
Curcumin Cystic fibrosis Double emulsion-
evaporation
(w/o/w)
PVA Particle size > 10μm
MMAD: 3.12μm
FPF: 13.41%
71% release in 9h
Hu etal. (2018)
431
Poly(lactic acid)/poly(lactic-co-glycolic acid) particulate carriers forpulmonary drug…
1 3
Table 2 Inhalable poly(lactic acid)/poly(lactic-co-glycolic acid) (PLA/PLGA) nanoparticles (NPs) for local delivery of the drugs to the lung
Particles Drug Indication Preparation technique Excipients Particle properties and
outcome
References
PEG-PLGA NPs Ibuprofen Cystic fibrosis Emulsion- evaporation PEG, Polyaspartamide Particle size: 126.3
186.8nm
PDI: 0.1870.218
EE: 55.782.2%
Craparo etal. (2016)
Mannosylated PEG-PLA/
PLGA NPs
Surfactant protein A Pulmonary infectious Nanoprecipitation PEG, mannose Particle size: 140nm
PDI: 0.114
Increases invitro &
invivo macrophage
uptake
Ruge etal. (2016)
PLGA nanocomposite Rifampicin Tuberculosis Spray drying Mannitol Particle size: 213nm
(NPs), 2.13.2μm
(MPs)
In vivo uptake by alveolar
macrophages in the
lungs
Ohashi etal. (2009)
PLGA NPs Tobramycin Cystic fibrosis Spray drying Spherical hollow porous
particles
Geller etal. (2007)
PLGA
Nanocomposite
Colistin Cystic fibrosis Emulsion-solvent diffusion PVA, chitosan, lactose,
mannitol
Particle size: 267nm
PDI: 0.150.18
EE: 63%
Prolonged efficacy
d’Angelo etal. (2015)
Magnetic-PEG-PLGA
NPs
SiRNA Lung cancer Double emulsion- solvent
diffusion
PEG Lower gene expression of
telomerase
Fekri Aval etal. (2016)
PLGA Nanocomposite Rifampicin Tuberculosis and lung
cancer
Emulsion-evaporation PVA, arginine, leucine Particle size: 190207nm
(NPs), 8.211.5µm
(nanocomposite)
MMAD: 0.6511µm
FPF: 13.432.63%
Yield: 3368%
EE: 4365%
Takeuchi etal. (2017)
PLGA NPs Levofloxacin Pulmonary P. aeruginosa
biofilm infections
Single and double
emulsion-evaporation
PVA, PEG, Lecithin,
Tyloxapol, Chitosan
Single emulsion: 200
240nm, EE 1523%
Double emulsion: 110
360nm, EE 622%
Multi-phase double emul-
sion: 170720nm, EE
411%
Good antibacterial activity
Cheow and Hadinoto
(2010)
PLGA NPs/MPs Tobramycin Cystic fibrosis Double emulsion- solvent
diffusion
PEG,
7-amino-4-methyl-3-cou-
mariny lacetic acid
EE: 2.43.6%
Particle size: 896902nm,
228233nm
Ernst etal. (2018)
432 F.Emami et al.
1 3
MMAD mass median aerodynamic diameter, ED emitted dose %, FPF fine particle fraction %, EE encapsulation efficiency %, PDI polydispersity Index, PVP polyvinyl pyrrolidone, PVA polyvi-
nyl alcohol, PEI polyethyleneimine, PEG polyethylene glycol, DOTAP dioleoyltrimethylammoniumpropane; SDS sodium dodecyl sulfate
Table 2 (continued)
Particles Drug Indication Preparation technique Excipients Particle properties and
outcome
References
PLGA NPs Ciprofloxacin Cystic fibrosis Nanoprecipitation Pluronic F68 Particle size: 190.4nm
PDI: 0.089
EE: 79%
Türeli etal. (2017)
PLGA NPs Ciprofloxacin Cystic fibrosis Nanoprecipitation Pluronic SDS Particle size: 145.2
979.8nm
PDI: 0.051.0
EE > 65%
Türeli etal. (2016)
PLGA NPs Ethionamide Tuberculosis Solvent evaporation PVA, mannitol Particle size: 225.7nm
PDI: 0.216
MMAD:1.8μm
FPF: 94.38%
ED: 97.22%
95% release in 24h
Debnath etal. (2017)
DOTAP-modified PLGA
NPs
siRNA Severe lung
diseases
Spray drying PVA, Mannitol, Lactose,
Trehalose
Smooth/raisin particles
MMAD: 2.25.6μm
Low water content: 0.78%
w/w
Yield: 19.356.4%
Jensen etal. (2010)
PEG-PLGA nanocom-
posite
pDNA Cystic fibrosis Double emulsion-solvent
evaporation (w/o/w)
PEI, Lactose Particle size: 166246nm
PDI: 0.2160.092
MMAD: 3.86.6μm
FPF: 17.434.2%
Enhanced luciferase
expression
Kolte etal. (2017)
PLGA NPs Ethionamide Tuberculosis Emulsion- evaporation PVA Particle size: 225.7nm
PDI: 0.216
MMAD: 1.79μm
FPF: 4.38%
ED: 97.22%
90% release in 24h
Debnath etal. (2017)
PEG-PLA NPs Lung diseases Solvent displacement PEG, Stearylamine,
Tween 80
Particle size:
Anionic NPs: 129.3nm
Cationic NPs: 141.3nm
Harush-Frenkel etal.
(2010)
433
Poly(lactic acid)/poly(lactic-co-glycolic acid) particulate carriers forpulmonary drug…
1 3
The DOX-LPM with a geometric diameter of 14μm and
aerodynamic diameter of 3.6μm showed successful aero-
dynamic behavior—they were deposited in the lungs and
remained for up to 2weeks. In a mouse model of B16F10
melanoma metastasis, there was a significant anti-tumor
effect in the DOX-LPM-treated group when compared with
the untreated group.
Nishimura etal. constructed porous and non-porous
PLGA MPs for inhalation by using a single-step emulsion-
evaporation method (Nishimura etal. 2017). They prepared
porous particles having a geometric diameter of 510µm
with very low tapped density (0.04g/cm3). The particles
with a geometric diameter of 5µm showed lower emitted
dose and higher fine particle fraction (FPF) than those with a
geometric diameter of 10µm. PLGA MPs that were prepared
in the presence of Tween 85 were non-porous, and they had
the highest emitted dose with the lowest FPF, indicating a
weak aerosol performance. From this observation, it was
suggested that an electrostatic attraction force between the
porous particles and the capsules decreased the emitting effi-
ciency of the MPs from the capsules. Their study showed
that the aerodynamic diameter of the porous PLGA particles
was approximately 5µm with an approximate FPF value of
40–65%; however, the aerodynamic diameter of the non-
porous particles was approximately 14µm with a lower FPF
(< 20%). These results indicate that the porous particles had
unique internal structures and proper aerodynamic proper-
ties attributable to the spontaneous emulsion preparation.
Therefore, porous PLGA MPs can provide a suitable aero-
dynamic diameter for inhalation and deposition in the lungs
Table 3 Inhalable poly(lactic acid)/poly(lactic-co-glycolic acid) (PLA/PLGA) particles for peptides, proteins, genes, or other systemic drug
delivery systems
MMAD mass median aerodynamic diameter, ED emitted dose %; fine particle fraction %, EE encapsulation efficiency %, PDI polydispersity
Index, PVP polyvinyl pyrrolidone, PVA polyvinyl alcohol, HPβCD hydroxypropyl-β-cyclodextrin, PEI polyethyleneimine, PEG polyethylene
glycol, SDS sodium dodecyl sulfate, PEMA poly(ethylene-alt-maleic anhydride), BSA bovine serum albumin, EPO erythropoietin
Particles Drug Indication Preparation tech-
nique
Excipients Particle properties
and outcome
References
PLGA
MPs
Rosiglitazone Diabetes and pul-
monary arterial
hypertension
Double emulsion-
evaporation
(w/o/w)
PVA, PEI MMAD: 6.92μm
Release: 87.9% in
24h
Rashid etal. (2018)
Large porous
PLGA MPs
Insulin Diabetes Double emulsion-
evaporation
HPβCD, phenol-
phthalein, Tween
80, PVA
Particle size:
25.131.4µm
MMAD: 1019μm
EE: Insulin 52
100%
EE: HPβCD 24
60%
Ungaro etal. (2006)
Albumin-coated
porous hollow
PLGA MPs
Palmityl-
acylated
exendin-4
Diabetes Double emulsion-
evaporation
(w/o/w)
PEMA, HPβCD,
NaCl
Particle size:
17.2μm
MMAD: 3.2μm
Kim etal. (2011)
PLGA MPs BSA Vaccine delivery Supercritical
CO2-spray drying
l-leucine Particle size:
9.610.6μm
MMAD: 1.7
3.5μm
FPF: 25.443.4%
ED: 95.399.6%
Tavares etal. (2017)
PEG-PLGA NPs DNA, Protein
EPO
– Emulsion-solvent
evaporation
PVA, PEG Particle size:
160191nm
PDI:0.070.14
Bi-phasic drug
release
Menon etal. (2014)
Hallow PLGA MPs DNA Double emulsion-
evaporation
(w/o/w)
Pluronic L92 Particle size:
7.85µm
Span: 1.5
MMAD: 3.8µm
Density: 0.24g/
cm3
EE: 1528%
Mohamed and van
der Walle (2006)
PLGA-chitosan
MPs/NPs
Calcitonin Osteoporosis Emulsion-solvent
diffusion
Span 80, PVA,
Chitosan
Particle size:
660nm (NPs),
7.07µm (MPs)
Yamamoto etal.
(2005)
434 F.Emami et al.
1 3
to achieve high and efficient delivery of therapeutic agents
to the lung.
Nano‑in‑microparticles (Nanocomposites)
NPs as polymeric carriers for respiratory delivery have the
ability to enter the intracellular compartments and evade the
alveolar macrophages and mucociliary clearance mecha-
nisms, resulting in enhanced bioavailability and prolonged
drug residence time (Rogueda and Traini 2007). Moreover,
NPs can be modified for drug targeting to a specific lung
tissue and cell populations (Hillaireau and Couvreur 2009).
The interaction of NPs with lung tissue often depends on
the size and surface charge of the particles. Hence, adequate
engineering of particles at the nanosize level to produce NPs
with different features (size, morphology, and zeta-potential)
is an important aspect with excipient selection and formula-
tion design (Lai etal. 2009).
However, the pulmonary delivery of NPs has two major
drawbacks: NPs, with the exception of particles < 50nm, are
generally exhaled upon inhalation, and they are prone to aggre-
gation owing to their high surface energy (Rogueda and Traini
2007; Yang etal. 2008). To overcome these drawbacks, the
most widely employed inhalation approach is the nebulization
of aqueous dispersions of NPs. However, this approach can
generate problems with instability of the nanosuspensions, such
as aggregation and/or drug leakage (Dailey etal. 2003). These
problems can be overcome by applying NPs as dry powder.
Direct drying of NPs suspensions has been shown to have some
success in generating dry powders composed of agglomerated
PLGA NPs, but with this approach, it may be difficult to pre-
serve the integrity of NPs, including in terms of inappropriate
overflow and aerosolization properties (Ungaro etal. 2012). As
an alternative approach, particles obtained by the embedding
of drug-loaded PLGA NPs within sugar MPs have been sug-
gested to improve the formulation stability and aerodynamic
properties of the entrapped NPs (Al-Qadi etal. 2012; Sham
etal. 2004). The NPs-incorporated MPs, also termed nano-in-
microparticles, are designed to release primary NPs from inert
microcarriers into lung lining fluid after reaching the alveolar
surface (Abdelaziz etal. 2018; Ungaro etal. 2012).
Preparation ofinhalable PLA/PLGA particles
Several studies have investigated the various preparation
methods for polymeric MPs/NPs and their applications for
pulmonary DDS (Bailey and Berkland 2009; Menon etal.
2014; Mundargi etal. 2008). The conventional methods
used in the production of NPs and MPs involve single/dou-
ble emulsion-solvent evaporation, spray freeze drying, spray
drying, supercritical fluid drying, and coacervation (Fig.2).
Each process has its advantages as well as limitations (Cam-
pardelli etal. 2016; Emami etal. 2018a).
Single/double emulsion‑solvent evaporation
technique
Emulsion-solvent evaporation method has been extensively
applied to prepare biodegradable polymeric carriers for
Fig. 1 Different types of
polymeric poly(lactic acid)/
poly(lactic-co-glycolic acid)
(PLA/PLGA) particles as carri-
ers for pulmonary drug delivery
Inhalable
PL
A/PLGA
Particles
Microparticles
Large porous
microparticles
Nano-in-
microparticles
Polymeric matr
ix
Drug
Pore
Polymeric matrix
Drug
Nanoparticle
Drug
435
Poly(lactic acid)/poly(lactic-co-glycolic acid) particulate carriers forpulmonary drug…
1 3
respiratory drug delivery (Patil and Sarasija 2012). This
technique involves the preparation of oil/water emulsion and
subsequent removal of the organic phase through evapora-
tion procedure. The oil phase diffuses out of the polymer
matrix into the water phase and finally is evaporated, pro-
ducing drug-encapsulated polymeric MPs/NPs (Patil and
Sarasija 2012). One of the easiest procedures used in the
preparation of MPs and NPs is the single emulsion-solvent
evaporation method. Hydrophobic drugs are dissolved with
polymer in an organic phase, which are then emulsified in
an aqueous phase. Different types of emulsions, such as oil
in water (o/w), oil in oil (o/o), or water in oil (w/o), were
prepared by exposure to a high shearing energy, includ-
ing homogenizing, ultrasonication, or milling. The organic
phase is evaporated under vacuum or low pressure by the
extraction method. The tailored particle is then lyophilized
for long-term storage (Lee etal. 2016).
For hydrophilic drugs, the double w/o/w emulsion–sol-
vent evaporation process has been widely employed. How-
ever, this technique often results in low drug loading owing
to the difficulty in controlling the migration of hydrophilic
drugs from the inner to the outer aqueous phase. Some
formulation approaches have been applied to enhance the
incorporation efficiency of hydrophilic drugs including the
adjustment of aqueous phase pH, ion-pairing using counter
ions to drug molecule, and addition of fatty acid to organic
phase (Govender etal. 1999; Holmkvist etal. 2016). For the
preparation of PLGA MPs of a water-soluble drug—levo-
floxacin, Gaspar etal. added fatty acid (lauric acid) to the
oil phase or the saturated aqueous phase with levofloxacin
to avoid the escape of the drug from the organic phase in
the w/o/w emulsion, resulting in a higher drug encapsula-
tion when compared with the conventional double emul-
sion method (Gaspar etal. 2019). Although the addition of
lauric acid resulted in a larger particle size and no sustained
release, the saturation of the aqueous phase with levofloxa-
cin resulted in an appropriate particle size for inhalation
(~ 5µm) and a controlled drug release.
Spray drying
Spray drying (SD) is the commonly used particle engi-
neering method for the preparation of particles with appro-
priate size and morphology for pulmonary delivery (Mut-
til etal. 2007; Nandiyanto and Okuyama 2011). The SD
method includes three phases comprising of atomization,
W/O or O/W
emulsion
Single
emulsion
evaporation
Double
emulsion
evaporation
Spray
freeze
drying
Supercritical
fluid drying
Spray
drying
Nanoprecipitation
Emulsion
+
Oil phase (O)Water phase (W)
Drying
chamber
Heated gas
cyclone
Exhaust
gas
Polymer
solution
Polymer
solution
CO2
Polymer
solution
Frozen
Droplets
Ice
Liquid
N2
Fig. 2 Preparation techniques of poly(lactic acid)/poly(lactic-co-glycolic acid) (PLA/PLGA) particles for pulmonary drug delivery
436 F.Emami et al.
1 3
drying in the hot chamber, and separation of particles. The
feeding solution is atomized through nozzles into a drying
chamber. The generation of polymeric droplet and subse-
quent dehydration are performed in a chamber with hot
air flow. The dried powders are transferred into a cyclone
(Faghihi etal. 2014; Nandiyanto and Okuyama 2011;
Ramezani etal. 2013). Yamamoto etal. prepared insulin-
loaded PLGA nanocomposite particles for inhalation by
the spray-fluidized bed granulation method (Yamamoto
etal. 2007). At first, PLGA NPs were prepared, insulin
was encapsulated, and finally nanocomposites were pre-
pared. Briefly, PLGA and 6-coumarin were dissolved in
an organic solvent mixture, and the resulting solution was
injected into polyvinylalcohol solution. The evaporation
of the organic solvent resulted in NPs with an average
size of 250nm. Next, lyophilized powder and mannitol
were suspended in the aqueous phase and spray-dried in
a fluidized bed granulation system. In this method, the
feeding solution was sprayed into the hot chamber, and
the spray-dried particles are dispersed into the granula-
tion zone by a rinsing pulsed air jet. Finally, NPs were
granulated by the coalescence of wet particle collision,
which resulted in the formation of nanocomposites. The
average aerodynamic diameter of the tailored particles was
reported to be 1–10µm, as measured by cascade impac-
tion. The nanocomposites exhibited greater aerodynamic
performance than that by freeze-dried NPs. The nanocom-
posite granules demonstrated preferable physicochemical
characteristics for inhalation and lung dispersion in both
invitro and invivo studies.
Spray freeze drying
Spray freeze drying (SFD) method combines the advantages
of both SD and freeze-drying techniques (Abdelaziz etal.
2018). Furthermore, this method can overcome the limita-
tions of SD method for heat sensitive molecules. In SFD
process, a feeding solution is atomized through a nozzle
into a vapor above liquid nitrogen, frozen in liquid nitro-
gen, and subsequently lyophilized in a freeze dryer (Emami
etal. 2018a, b). Ali and Lamprecht studied the SFD pro-
cedures used for the synthesis of inhalable nanocomposite
microcarriers suitable for pulmonary deposition (Ali and
Lamprecht 2014). In this study, spray freeze-dried MPs with
an aerodynamic diameter of 3.0 ± 0.5µm were prepared,
and they had larger specific surface areas (6777m2/g) and
lower densities (0.02g/cm3) than those of the MPs similarly
prepared by SD method. The SFD showed better perfor-
mance than SD in terms of maintaining the particle size of
NPs following reconstitution. Furthermore, SFD provided
highly porous MPs with proper aerodynamic diameters for
inhalation.
Supercritical uid drying
A particle generation process using supercritical fluids
(SCF) has been proposed for the preparation of polymeric
particles by dehydration in the absence of extreme tempera-
ture (Campardelli etal. 2012; Tavares etal. 2017). SCF dry-
ing (SCFD) uses materials such as carbon dioxide or metha-
nol above its critical pressure and temperature. The critical
temperature of a liquid is the temperature at which its vapor
cannot be liquefied. The pressure that is required to condense
a gas at its critical temperature defines its critical pressure.
SCF above its critical point exhibits the appropriate charac-
teristics of gas and liquid, including the flow characteristics
of a gas (low viscosity) and the solubility of a solute. SCF
has the potential to penetrate within materials because they
do not exhibit any surface tension, and the solvent power is
proportional to their density. SCFD is a tunable procedure
that can control the density of SCF and the solubility of a
solute by altering the pressure or temperature used during
the process (Emami etal. 2018b). Carbon dioxide is the most
frequently used SCF because it is nontoxic, inexpensive, and
nonflammable. It also has a low critical point (31.1°C and
73.8bar), which makes it suitable for thermo-sensitive drugs
at minimal procedure cost (Tavares etal. 2017).
Tavares etal. constructed dry powder PLGA MPs by
supercritical carbon dioxide-assisted SD (SCF-SD) for
vaccine delivery to the lung (Tavares etal. 2017). Vaccine
formulations were prepared using bovine serum albumin
(BSA) as a model vaccine in the presence of l-leucine. The
aerodynamic performance of dry powder inhaler was charac-
terized using the Andersen cascade impactor. Tailored BSA-
PLGA particles showed fine particle fraction of 43.4% with
an aerodynamic diameter of 1.7–3.5μm, which represents
the proper characteristics for inhalation. The authors con-
cluded that the addition of l-leucine in BSA formulation
as a dispersibility enhancer could overcome the stress in
SCF-SD method. In addition, they demonstrated that the
SCF-SD process is appropriate for the preparation of PLGA
dry powder inhaler.
Nanoprecipitation
Nanoprecipitation involves crystallization and precipita-
tion using anti-solvent jets. Crystalline drug particles with
proper size distribution are produced by controlled crystal-
lization. Inhalable NPs can be prepared by rapid precipi-
tation using anti-solvents. In addition, ultrasonic radiation
has been applied to control precipitation. Various drugs
against asthma were prepared using the sonocrystalliza-
tion technique (Patil and Sarasija 2012). Recently, Türeli
etal. constructed ciprofloxacin-loaded PLGA NPs against
Pseudomonas aeruginosa infections in cystic fibrosis (Türeli
etal. 2017). PLGA NPs were prepared by an optimized
437
Poly(lactic acid)/poly(lactic-co-glycolic acid) particulate carriers forpulmonary drug…
1 3
nanoprecipitation method using Microjet Reactor. The tai-
lored particles had a particle size of 190.4 ± 28.6nm with
polydispersity index of 0.089 and encapsulation efficiency
of approximately 79%. Compared with the native drug, cip-
rofloxacin-loaded PLGA NPs showed greater anti-microbial
activity and reduced mucus turbidity in an invitro assay.
Additionally, the NPs demonstrated acceptable stability in
the mucus. The authors concluded that ciprofloxacin-loaded
biodegradable PLGA NPs efficiently offer promising treat-
ment strategies for chronic pulmonary infections (Türeli
etal. 2017).
Applications ofPLA/PLGA particles
topulmonary drug delivery
Local drug delivery
An effective local drug delivery is the obvious choice for
treating lung diseases such as tuberculosis, COPD, cystic
fibrosis, asthma, and lung cancer (Pison etal. 2006). Tables1
and 2 summarize the PLA/PLGA MPs and NPs studied for
local drug delivery against various respiratory diseases. For
respiratory diseases, drug delivery with a novel targeting
agent to the lung is required for adequate drug concentra-
tions at the pathology site, with minimal systemic absorption
and undesired side effects. An ideal inhaler should provide
sustained effects, retain drugs within the lung, reduce the
prescription frequency, and enhance patients’ compliance
with the therapeutic regimen (Yang etal. 2009). Polymeric
MPs/NPs retained in the lungs have the potential to pro-
vide high drug concentration and prolonged drug residence
time in the lung with minimum drug exposure to the blood
circulation (Harush-Frenkel etal. 2010). Lu etal. encapsu-
lated recombinant Mycobacterium tuberculosis antigen 85B
(Ag85B) by SD method into PLGA MPs for the treatment
of tuberculosis (Lu etal. 2007). PLGA MPs of 34μm were
suitable for targeting macrophages and for aerosol delivery
to the lung. PLGA-rAg85B MPs were able to stimulate an
antigen response that was twofold higher than that by the
pure rAG85B.
Systemic drug delivery
Respiratory drug delivery provides a non-invasive route of
drug administration targeting the systemic blood circulation,
as the lungs have a large alveolar surface area, rich blood
vascularity, and thin epithelial barrier (Rytting etal. 2008;
Sung etal. 2007). Moreover, first-pass metabolism effect can
be minimized by pulmonary delivery, which can be a good
alternative delivery system for therapeutic peptides and pro-
teins (Rytting etal. 2008). The pulmonary delivery of thera-
peutic proteins and peptides, such as calcitonin (Poursina
etal. 2016), trastuzumab (Ramezani etal. 2014), and insu-
lin (Exubera® and Afrezza®) (Al-Tabakha 2015), have been
investigated for the treatment of osteoporosis, breast cancer,
and diabetes, respectively(Table3). For systemic delivery
through the pulmonary route, some specific physical barri-
ers, such as blood proteolytic degradation, renal clearance,
and hepatic first-pass metabolism, should be considered, and
an effective dosage form of the drug is highly required to
be absorbed through the alveolar and bronchial epithelium
(Depreter etal. 2013). The low permeability of the mem-
brane to macromolecules is one of the restricting factors in
crossing the alveolar capillary membrane. The absorption
of peptides and proteins through the double-layered phos-
pholipid membrane by diffusion is restricted owing to their
large size and hydrophilic nature. The absorption kinetics
of therapeutic proteins into the systemic blood circulation
are usually inversely related to the molecular weight, with
lower molecular weights resulting in a lower “time of maxi-
mum concentration” (Tmax) and higher “maximum plasma
concentration” (Cmax) (Hu etal. 2016). Some approaches
can enhance the adsorption of peptides and proteins through
the capillary membrane in the lungs. Absorption enhanc-
ers, including bile salts, surfactants, chitosan, citric acid,
cyclodextrins, and lipid-based particles (liposomes and solid
lipid NPs), are recommended to overcome the low absorp-
tion (Emami etal. 2018b). The polymeric carriers can also
protect the drug from physicochemical and enzymatic deg-
radations (Campardelli etal. 2016).
Vaccine delivery
There have been many studies of PLGA particles applica-
tion for the delivery of vaccines to induce efficient immunity
in various diseases such as hepatitis B, tuberculosis, chla-
mydia, leishmaniasis, toxoplasmosis, and malaria (Allah-
yari and Mohit 2016). The PLGA particles could achieve
a long-lasting effect in different disease models; hence, the
need for multiple injections associated with conventional
vaccines can be avoided (Dewangan etal. 2018; Saini etal.
2011). In a study by Feng etal., a single subcutaneous
injection of PLGA MPs loaded with recombinant hepati-
tis B surface antigen (HBsAg) in mice resulted in antibody
responses comparable to those of three injections of the
conventional HBsAg vaccine (Feng etal. 2006). MPs have
been used frequently to improve vaccine delivery, in which
PLGA MPs with diameters 110µm are capable of interact-
ing with antigen presenting cells to induce cell-mediated
immunity (Audran etal. 2003; Vordermeier etal. 1995).
Antigen-loaded PLA or PLGA particles could enter the
phagosome/phagolysosome and transport some antigens to
the cytoplasm (Men etal. 1999). Furthermore, polymeric
MPs could induce immune responses and mucosal immuni-
zation (O’Hagan etal. 1998). Antigens loaded in MPs could
438 F.Emami et al.
1 3
more efficiently present antigen to macrophages by 100- to
1000-fold and offer superior immunization in comparison
with the soluble antigen (Lu etal. 2007).
Protein andpeptide delivery
The therapeutic use of biomolecules has been substantially
increased by the development of biotechnology techniques,
and various peptides and proteins have been shown to have
therapeutic potential against various diseases. However,
these biomolecules have therapeutic limitations owing to
chemical and physical instability, high susceptibility to pro-
teolytic degradation, and short circulation half-life requiring
multiple injections (Mundargi etal. 2008; Song etal. 2017).
Several strategies for sustained parenteral form and alter-
native administration route of drugs have been suggested
as solutions to the therapeutic limitations of biomolecules
(Shire etal. 2004; Tyler etal. 2016). Although the inhaled
application of encapsulated proteins and peptides into PLA/
PLGA particles seems to be a method of choice, some pre-
conditions should be considered to ensure the administration
of sufficient and reproducible drug doses for the treatment
of systemic diseases. It is difficult to achieve efficient bio-
availability with the pulmonary delivery of macromolecules
because of local toxicity, immunogenicity, large size of mac-
romolecules, humidity, mucociliary clearance, presence
of hydrolytic enzymes, and macrophage clearance (Agra-
hari etal. 2016). Furthermore, the stability issue of pep-
tides incorporated into PLGA MPs needs to be considered
because several peptide drugs such as calcitonin, octreotide,
goserelin, and leuprolide are acylated by their interaction
with PLGA structures (Ahn etal. 2011; Guo etal. 2019; Na
and DeLuca 2005; Na etal. 2003, 2007; Park etal. 2007;
Shirangi etal. 2016).
Gene delivery
Polymeric particles are favorable in the drug delivery
of nucleic acids to the lung owing to the localized effect
and the reduced systemic side effects (Jensen etal. 2010;
Menon etal. 2014). The traditional delivery of DNA are
restricted by enzymatic degradation, limited bioavailability,
and physicochemical instability, but the polymeric system
can overcome these limitations because of the large alveolar
surface area for rapid cellular uptake, prolonged retention
of the drug, and lower effective dose providing lower tox-
icity risk compared with systemic delivery (Menon etal.
2014). Jensen etal. studied SD of siRNA-loaded PLGA NPs
into nanocomposite MPs for pulmonary DDS (Jensen etal.
2010). The siRNA-loaded NPs were prepared by the double
emulsion-evaporation technique, and the nanocomposite was
then synthesized using SD of PLGA NPs suspension in the
presence of various carbohydrates (mannitol, trehalose, and
lactose). The optimum formulation of siRNA-loaded nano-
composite prepared in the presence of mannitol resulted in a
product with low moisture content (0.78% w/w) and a good
aerodynamic diameter for inhalation. The invitro results
showed that there was no significant difference between
the biological activity of the siRNA extracted from siRNA-
PLGA nanocomposite and that from unmodified siRNA.
Similarly, siRNA-PLGA NPs mixed with lipofectamine
2000 downregulated (68%) the enhanced green fluorescent
protein expression in H1299 non-small lung cancer cells,
indicating that the biological activity of the siRNA was con-
served with the SD method.
Kolte etal. reported composite NPs of the PLGA and
polyethyleneimine (PEI) as an alternative to viral and lipo-
somal vectors for the pulmonary delivery of pDNA (Kolte
etal. 2017). NPs with different weight ratios of PLGA/PEI
were prepared by double (w/o/w) emulsion solvent evapo-
ration method. The encapsulation efficiency of pDNA was
increased by the addition of PEI. The invitro cell uptake
and transfection studies revealed that NPs with 10% w/w
PEI were more efficient, but they exhibited significant
cytotoxicity. PEGylation of these composite NPs reduced
their toxicity and enhanced the cellular uptake and pDNA
expression. PEGylation also improved the diffusion of NPs
through the mucus barrier and inhibited the uptake of NPs
by macrophages of the lung. Finally, PEGylated composite
NPs were freeze-dried with lactose carrier particles, result-
ing in improved aerosolization properties and lung deposi-
tion, without influencing the bioactivity of pDNA.
Conclusions
The numbers of polymeric particulate systems for pulmo-
nary therapeutic applications have increased with the wide-
spread use of biocompatible polymers. PLA and PLGA are
attractive biopolymers useful for inhalable particle formula-
tions owing to their biocompatibility and biodegradability.
MPs and NPs obtained by different manufacturing tech-
niques with PLA or PLGA have demonstrated significant
potential as carriers for various local or systemic respiratory
applications. The manufacturing techniques of PLA/PLGA
MPs and NPs involve single/double emulsion-solvent evapo-
ration method, spray drying, spray freeze drying, supercriti-
cal fluid drying, and nanoprecipitation. Adequately designed
and engineered MPs and NPs can contribute to desirable
pulmonary drug delivery characterized by sustained drug
release to the lungs, prolonged drug action, reduction in
therapeutic dose, low adverse effects, and improved patient
compliance.
In the development of inhalable DDS, significant progress
has been made by using liposomes with Alveofact® approved
439
Poly(lactic acid)/poly(lactic-co-glycolic acid) particulate carriers forpulmonary drug…
1 3
by FDA in 1990 for the treatment of acute respiratory dis-
tress syndrome and Arikace® (drug: amikacin) approved
by FDA in 2018 for the treatment of Mycobacterium avium
complex lung disease (Paranjpe and Muller-Goymann 2014;
Shirley 2019). However, liposomes are prone to instability
problem with the possibility of drug leakage during storage.
Compared with liposome, polymeric MPs and NPs present
higher structural integrity providing enhanced stability,
higher drug loading, and prolonged drug release (Abdelaziz
etal. 2018). Therefore, biodegradable PLA/PLGA-based
MPs and NPs are highly beneficial carrier option for both
local and systemic inhalation therapies.
Acknowledgements This work was supported by the National
Research Foundation of Korea (NRF) grant funded by the Ministry of
Science and ICT (NRF-2018R1A2B3004266).
Compliance with ethical standards
Conflict of interest The authors declare that they have no conflict of
interest.
Statement of human and animal rights This article does not contain
any studies with human and animal subjects performed by any of the
authors.
Open Access This article is distributed under the terms of the Creative
Commons Attribution 4.0 International License (http://creativecommons.
org/licenses/by/4.0/), which permits use, duplication, adaptation, distri-
bution and reproduction in any medium or format, as long as you give
appropriate credit to the original author(s) and the source, provide a link
to the Creative Commons license and indicate if changes were made.
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... In the free cy5.5 treatment group, significant biodistribution in other organs and a weak fluorescence signal in the tumor was observed, indicating the rapid clearance of cy 5.5 from the TME, which is attributed to the lipophilicity and small size, which enhanced the recognition and uptake of cy5.5 by the liver and spleen [100,101]. Although small AuNP (< 5.5 nm) are preferable for renal excretion, large AuNP (> 5.5 nm) are desirable for long blood circulation and tumor localization, [102], which show accelerated sequestration in the liver and spleen [103]. ...
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