Overall, it is evident that polymer-based nanoparticles could con-tribute to a promising tumor-targeted drug delivery system with great potential in colorectal cancer therapy.. Poly La
Trang 1Current Pharmaceutical Design, 2016, 22, 000-000 1
1381-6128/16 $58.00+.00 © 2016 Bentham Science Publishers
Nanoparticulate Drug Delivery to Colorectal Cancer: Formulation Strategies and Surface Engineering
Thao Truong-Dinh Tran1,3, Phuong Ha-Lien Tran2, Yichao Wang4, Puwang Li1 and Lingxue Kong1,*
1Institute for Frontier Materials, Deakin University, Waurn Ponds, Victoria 3216, Australia; 2School of Medicine,
Deakin University, Waurn Ponds, Victoria 3216, Australia; 3Pharmaceutical Engineering Laboratory, Biomedical
Engineering Department, International University, Vietnam National University – Ho Chi Minh City, Vietnam;
4School of Electrical and Computer Engineering, RMIT University, Melbourne, Australia
Abstract: The evolution of polymer-based nanoparticle as a drug delivery carrier has greatly contributed to the
de-velopment of advanced nano and micro-medicine in the past few decades The polymer-based nanoparticles of
bio-degradable and biocompatible polymers such as poly (lactide-co-glycolide) and chitosan which have been
ap-proved by Food & Drug Administration and/or European Medicine Agency can particularly facilitate the
maintain-ing of specific properties for a real transition from laboratory to the clinical oral and parental administration This
review presents an overview of the strategies of preparing polymeric nanoparticles and using them for targeting
co-lorectal cancer Theranostics and surface engineering aspects of nanoparticle design in colonic cancer delivery are
also highlighted
Keywords: Nanoparticles, poly (lactide-co-glycolide), chitosan, colorectal cancer, theranostic, surface engineering
1 INTRODUCTION
Colorectal cancer is one of the major universal public health
problems and causes of death worldwide [1, 2] A major draw-back
of conventional formulations for colorectal cancer is their side
ef-fects and toxicity caused by the distribution of drug around the
body due to its design in systematic delivery therapeutics [3, 4] In
other words, these approaches to colorectal cancer treatment are
nonspecific One of other major limitations of some promising
anti-cancer drugs such as docetaxel and paclitaxel is the insolubility
property in water and therefore, leading to the poor absorption and
bioavailability of these drugs [5, 6] Targeted drug delivery,
there-fore, is one of indispensable strategies against this type of cancers
by state-of-the-art techniques of controlled solid dosage forms or
micro/nanoparticles to improve solubility and bioavailability, and
enhance drug distribution to the target organ The delivery would
also improve the stability of model drugs while also reducing
sys-temic side-effects [7-9] Potential applications of nanoparticles have
been demonstrated by 40 nanomedicine products that have been
approved for clinical use in the past two decades [10]
Polymer-based nanoparticles have received particular attentions
in design and fabrication of targeted drug delivery systems recently
Overall, it is evident that polymer-based nanoparticles could
con-tribute to a promising tumor-targeted drug delivery system with
great potential in colorectal cancer therapy The shortcoming of
these potential approaches, however, should also be evaluated
care-fully Information on the development of current strategies for
tar-geted colorectal cancer summarized in this review would give the
readers a general but deep understanding of practical approaches
and effective carriers that can be applied in targeted colorectal
can-cer delivery (Fig 1)
Most of colorectal cancer survivals depend on how early the
stage at diagnosis is [11] Overcoming the lack of sensitive property
of current devices and the nature of small colorectal neoplasia of
the disease which hinder a successful treatment, a tool for
observa-tion and diagnosis of precancerous lesions would be a great
*Address correspondence to this author at Institute for Frontier Materials,
Deakin University, Waurn Ponds, Victoria, 3217, Australia; Tel/Fax:
+61352272087, ++61352271002; E-mails: lingxue.kong@deakin.edu.au
contribution to the field Here the imaging agents encapsulated in polymer-based nanoparticles are the subjects of the discussion Furthermore, efficient delivery of the nanoparticles with surface engineering are also outlined
2 CURRENT POLYMER STRATEGIES DEVELOPED FOR TARGETED COLORECTAL CANCER
2.1 Poly (Lactide-co-Glycolide) (PLGA)-Based Approaches
Since its discovery in the 1970, PLGA has become one of the most common and feasible polymers developed for controlled drug delivery among polymeric nanoparticles [12-16] It has been ap-proved by the U.S Food and Drug Administration as a material for use in medical applications and since then a number of drugs have been investigated to incorporate in PLGA encompassing laboratory products and commercial products with FDA approval [17-27] Typical structure of PLGA has been known as the hydrophobic synthetic and linear copolymer constructed by two different types
of monomer which are glycolic acid and lactic acid [28-31] The molar ratio of these monomers and molecular weight defines the
commercial form of PLGA and its physicochemical properties (Fig 2) [32-34] The crystal degree of PLGA depends on molecular
weight and this molar ratio (higher 70% glycolic indicates amor-phous state in nature) [35] The increase of the glycolic content in the ratio can result in less hydrophobic character and lower required degradation time of PLGA [36, 37] In the presence of water, these monomers will be released and then subjected to metabolism via the Krebs cycle easily [38], resulting in a minimal systemic toxicity associated with biocompatible and biodegradable properties of PLGA for controlled drug delivery [39-41] Therefore, PLGA has attracted many attentions and commonly used as a potential carrier for the encapsulation of anti-cancer drugs In addition, other spe-cific characteristics of PLGA such as drug degradation protection, sustained drug release, possibility of surface engineering to modify surface properties and targeted drug delivery make it become more promising in further applications [8, 12] Despite the widespread application of PLGA and different methods that have been used in designing nanoparticles for drug delivery, there have been few re-ports describing PLGA-based nanoparticles for targeted drug deliv-ery to colorectal cancer
Lingxue Kong
Trang 2Fig (2) Typical structure of a PLGA n= number of units of lactic acid; m=
number of units of glycolic acid For example, PLGA 50:50 identifies 50%
lactic acid and 50% glycolic acid
2.1.1 Emulsion Solvent Evaporation
PLGA-based nanoparticles have received tremendous attention
as a powerful drug delivery system for cancer-related diseases
Among various fabrication methods, the emulsion solvent
evapora-tion has been commonly reported as a potential technique for
tar-geted colorectal cancer In the method developed by Wang et al.,
[43], dichloromethane was used as organic solvent to dissolve
PLGA and paclitaxel – a poorly water-soluble drug The O/W
(oil-in-water) emulsion was formed by adding organic phase to aqueous
phase containing polyvinyl alcohol (PVA) Meanwhile, the particle
size was controlled by probe sonication This kind of technique is
quite simple and only allows the encapsulation of hydrophobic
drugs Alternatively, the double emulsion solvent evaporation
method was developed to encapsulate hydrophilic drugs instead of
hydrophobic drugs In previous research of targeted colorectal can-cer of 5-fluorouracil [42, 44, 45], while drug was dissolved in water
to obtain an inner aqueous phase, PLGA was dissolved in an or-ganic solvent The aqueous drug solution (W) was emulsified in the organic phase with a probe sonicator to form W/O (water-in-oil) emulsion which was then emulsified in PVA solution, resulting in
W/O/W emulsion Similarly, Sureban et al [46] have utilized this
technique to encapsulate DCAMKL-1 specific siRNA in PLGA nanoparticles They demonstrated that an inhibition of colorectal cancer tumor growth could be achieved by targeting DCAMKL-1
Detailed illustration of this method is shown in Fig (3)
2.1.2 Combination of Salting-Out and Emulsion Evaporation
This modification method was developed using water-miscible solvents and salting-out agents in the process of emulsion evapora-tion method For example, to explore the inhibievapora-tion of adenocarci-noma cells (HT-29) using meloxicam in PLGA nanoparticles, ace-tone (AC) was mixed with dichloromethane to dissolve PLGA and the model drug before pouring the mixture into an aqueous solution containing salting-out agent [47] AC was used as a water-miscible solvent to induce the formation of PLGA nanoparticles through the diffusion of AC into the aqueous phase [48-59] In addition to AC, MgCl2 was used as a salting-out agent which could cause the salt-ing-out effect by a sudden change in the salt concentration in the continuous phase of the emulsion under the dilution process [57, 59-61] Consequently, a stable O/W emulsion was expected to be obtained due to the prevention of phenomena commonly observed when an organic solvent is mixed with water [62] The most fre-quently used salting-out agents are MgCl2, magnesium acetate, NaCl
Fig (1) Current strategies of polymer-based nanoparticles for targeted colorectal cancer
O
O
O
H
O
O
H
Trang 3and CaCl2 [62, 63] Although this method can be useful for
encap-sulation of heat sensitive drugs and proteins that are agents
intro-duced in a process without temperature and with minimizing
ten-sion to protein encapsulants, respectively, the main disadvantage of
this method is the requirement of severe purification [8, 64, 65]
2.1.3 Nanoprecipitation
Usually, the nanoprecipitation method has been developed by
dropwising a polymer in an organic solvent into an aqueous phase
(anti-solvent) [66-69] It is also called the solvent displacement
method with one-step process In the effort of functionalizing
ap-tamer on PLGA containing curcumin nanoparticles as delivery
system to colorectal cancer cells [70], acetonitrile, an organic
solu-tion containing PLGA and curcumin, was added in the lipid
aque-ous phase containing lecithin and Pegylated phospholipid
(DSPE-PEG2000-COOH) for self-assembled formation of nanoparticles
Ethanol, methanol and AC instead of acetonitrile could be
consid-ered as alternative solvents of polymers in the nanoprecipitaion
method In addition, a surfactant could be added in the aqueous
phase for stabilization
Fig (4) Chemical structure of chitosan
2.2 Chitosan (CS)-Based Systems
There has been a wide trend of using CS in drug delivery
sys-tems recently, especially for gastrointestinal delivery due to
exhibi-tion of good mucoadhesive features, prolonged residence time in
the intestine and, subsequently, enhancing the bioavailability of the
drugs [71-76] Furthermore, it is a nontoxic and biocompatible
polysaccharide [77-80] With regards to a specific structure of a
weak base having pKa value of about 6.2 - 7.0 (Fig 4), pure CS can
be easily dissolved in an acidic environment with pH in the range
within stomach due to the protonation of amino groups [81-83] CS, therefore, usually needs a modification or nanoparticulate formula-tion in targeting oral delivery for colorectal cancer in spite of the well-known advantage of chitosan that can release therapeutic agents specifically at the colon by colonic microflora (glycosidic linkages degradation) [84-86]
2.2.1 Ionic Gelation
In this method, the electrostatic interaction between positive charged CS solution and negative charged salt solution was used in
preparation of CS nanoparticles [87-89] According to Li et al [90] and Jain et al [91, 92], this method was successfully applied in
preparation of CS nanoparticles for delivery of 5-fluorouracil and oxaliplatin in colorectal cancer therapy using sodium tripolyphos-phate solution as the negative charged solution Furthermore, the loading combination of 5-fluorouracil and leucovorin in CS nanoparticles by this method has resulted in a promising and effec-tive multiple anticancer drugs delivery system in the chemotherapy
of colorectal cancer [93] In addition to the therapeutic purpose in colonic delivery, another research used CS to develop a safe liver-targeting cytokine delivery system that exploited liver immunity to prevent colorectal liver metastasis [94] Using similar ionic gelation
method, Xu et al [94] demonstrated that the system where
inter-luekin-12 encapsulated in CS nanoparticles could trigger antitumor
immunity in the liver by the interleukin-12 accumulation Fig (5)
briefly illustrates the ionic gelation method in which CS was firstly dissolved in an aqueous solution and then, a solution of negatively charged drug(s) was dropped into CS solution under magnetic stir-ring at room temperature for the formation of CS nanoparticles The greatest advantage of this method is its simplicity and mild genera-tion which would be applied to most CS nanoparticle preparagenera-tion processes for colorectal cancer delivery [95-97]
2.2.2 Nanogels
More recently, a modified ionic gelation method has been de-veloped to prepare the chitosan-based nanogels According to
stud-ies of Feng et al [98, 99] with the purpose of improving oral
bioavailability of doxorubicin and mucoadhesive properties,
Fig (3) Illustration of double emulsion solvent evaporation [42]
Drug
PVA solution
Probe sonicator
Probe sonicator
O OH
O
NH2
O
OH
O
NH2
OH
O
NH2 OH
n
Trang 4
Fig (5) Illustration of the ionic gelation method [93]
chitosan-based nanogels were prepared by mixing CS solution
con-taining drug and tripolyphosphate under constant stirring The
de-signed formulation could be promising for the treatment of
colorec-tal cancer by prolonging and improving local drug concentration
2.2.3 Solvent Emulsication Evaporation
Similar to the solvent emulsification evaporation method in
preparing PLGA nanoparticles (Section 2,1), an organic solvent
was used for emulsification in addition to the aqueous CS solution
Commonly AC, dichloromethane [100], or even acetic acid [4] with
or without surfactant and stabilizer can be used as the organic
phase It has been noted that a high speed mixer emulsifier or a
high-speed homogenizer had to be used to emulsify the mixture in a
few hours for promoting particle formation Udompornmongkol et
al [100] was successful in encapsulating curcumin for targeted
human colorectal adenocarcinoma cell line (HT29) and human
colon carcinoma cell line (HCT116) using this method Tummala et
al [4] also successfully loaded 5-Fluorouracil to CS-based systems
for sustained release and localized drug in treatment of colorectal
cancer However, enteric-coating of CS nanoparticles should be
conducted as discussed in the surface engineering section below
2.2.4 Chitosan-Based Micelles
Hydrophobically modified chitosan by grafting or conjugation
with hydrophobic groups is an ideal strategy of forming CS
nanoparticles for tumor targeting With regards to amphiphilic
structure consisting of hydrophobic grafts on hydrophilic backbone,
micelle structure in aqueous medium with outer shell of hydrophilic
segments via hydrophobic interactions could be obtained through
the self-assembly process [9, 102-105] Hydrophobic drugs such as
curcumin and paclitaxel hence could be encapsulated in the core of
micelles which is hydrophobic Aiming at enhancing solubility and
stability of curcumin for improvement of antitumor activity and
inhibition of colorectal cancer stem cells, a formulation containing
curcumin in stearic acid-g-chitosan oligosaccharide polymeric
mi-celles has recently been developed [106] Stearic acid-g-chitosan
oligosaccharide, an amphiphilic polymer that could form micelles
in the aqueous medium and act as a polymer backbone for carrying drug, was introduced via a grafting reaction between the amino groups and carboxyl group [107] The results of this research demonstrated that the drug-encapsulated micelles inhibited colorectal cancer stem cells effectively [106] In another research, the amphiphilic doxifluridine-chitosan copolymer was synthesized
by grafting a prodrug of 5-fluorouacil (doxifluridine) and hydro-philic chitosan [108] The self-assembled micellar nanoparticles demonstrated the synergistic anticancer activity due to the sustained release of 5-fluorouracil via the slow conversion of doxifluridine
2.3 Albumin and Other Polymers
Recently, albumin (AL) has been another promising material that has drawn a tremendous attention in nanoparticle preparation due to its versatile applications, mild condition preparation and loading capacity of various molecules [109, 110] Moreover, given
a wide range of carrier types in drug delivery systems, albumin nanoparticles have been considered as a preferable delivery due to the capability of being easily adaptable to human body [110, 111]
A simple and well-known method to produce albumin nanoparticles
is coacervation that would be applied in preparation of albumin nanoparticles for targeted colorectal cancer [112, 113] For in-stance, 5-urouracil and cetuximab were successfully loaded in albumin nanoparticles and delivered to colon carcinoma cells in some recent reports [101, 114] Briefly, two basic consecutive steps including a desolvation agent addition for phase separation and rigidization of the coating are involved in the coacevation method
(Fig 6) In the first step, albumin is dissolved and incubated in a
suitable aqueous solution with or without drug Nanoparticles are formed by continuous dropwise of desolvation agent like ethanol under stirring at specific or room temperature In the second step,
an aqueous solution of a crosslinking agent, for instance, glutaral-dehyde, is added to the above solution to stabilize the resulting nanoparticles
Although popular polymers such as PLGA, CS and AL are most commonly used in a number of colorectal cancer therapeutics research, difficulties in the development of polymer-based nanoma-terials for biomedical applications still remain, which hinder the contribution of these polymers to the full potential benefit of thera-peutic nanoparticles Chemical modification/synthesis is a current strategy that could modulate the particle size, shape or state of these polymer-based systems The synthesis of halloysite-nanocomposite hydrogel was proposed to be more efficient for colon cancer deliv-ery [115] Sodium hyaluronate and poly (hydroxyethyl methacry-late) were chosen as biocompatible and biodegradable materials for hydrogel formation Subsequently, the encapsulation of 5-fluorouracil in the halloysite-nanocomposite hydrogel showed the pH-dependent drug release profile Another approach was ad-dressed to utilize the amphiphilic structure facilitating the self-assembly process to form the corresponding nanoparticles [10] It has been demonstrated that these 7-ethyl-10-hydroxy camptothecin micelle formulations were preferentially accumulated in tumors Higher anti-tumor efficacy and longer circulation time of the
mi-Fig (6) Illustration of coacevation method [101]
Trang 5
celles were observed as compared to that of a prodrug of
7-ethyl-10-hydroxy camptothecin (irinotecan) at an equivalent dose Very
recently, Le et al [116] reported that a hydrophilic
methoxy-poly(ethylene glycol)-b- poly[-(carbamic acid benzyl
ester)--caprolactone-co-amino--caprolactone] iblock copolymer was
syn-thesized via ring-opening polymerization This approach was
be-lieved to increase accumulation of nanocarriers with prolonged
release of 5-fluorouracil in vitro and in vivo
3 THERANOSTICS AND IMAGING AGENTS
The use of theranostic polymer-based nanoparticles is not quite
new in fabrication of drug delivery systems for biomedical
applica-tions In general there are three strategies in detection of colorectal
cancers
3.1 Iron oxide Nanoparticles (IONPs)
Among the imaging agents used, iron oxide nanoparticles
(IONPs) show their promising applications in biomedical
nanotech-nology [117] IONPs have be incorporated in the PLGA
nanoparti-cles by a proper method with the aims of developing
multifunc-tional nanoparticles for simultaneous targeted drug delivery,
mo-lecular imaging and therapeutic response monitoring or the
thermo-sensitivity of colorectal cancer (Fig 7) Generally, IONPs were
dispersed in an organic solution with or without PLGA before
en-capsulation For instance, in the study by Schleich et al [118],
PLGA was dissolved in dichloromethane containing IONPs and
using emulsion solvent evaporation method for encapsulation of
doxorubicin or paclitaxel This research suggested that these
nanoparticles with high uptake and magnetic characteristics not
only inhibited the CT26 cells growth but also supported the MRI
imaging In another research developed by Esmaelbeygi et al [1],
dichloromethane was also used to disperse IONPs However,
IONPs were encapsulated in PLGA nanoparticles by multiple
emul-sions–solvent evaporation methods Consequently, this drug
deliv-ery system was effective for the treatment of colorectal cancer due
to the assistance of harmful hyperthermia
Fig (7) Example of iron oxide-based multifunctional nanoparticles for
theranostics of colorectal cancer
3.2 5-Aminolaevulinic Acid
5-aminolaevulinic acid is known as a precursor during heme
group synthesis [119] In human body, it is totally degraded in the
cells and converted to protoporphyrin IX which is excited by
op-tima light to generate fluorescence in cancer lesions [120, 121]
Therefore, 5-aminolaevulinic acid is a promising material in
detect-ing malignant or premalignant tissue [122] Recent articles
ad-dressed this issue by encapsulation of 5-aminolaevulinic acid in
chitosan nanoparticles showed that these nanoparticles played a
significant role in fluorescent endoscopic detection [122-125]
3.3 Near-Infrared Fluorescence (NIRF) Imaging Dye
Like other imaging agents, NIFR imaging dye is encapsulated
in nanoparticles to improve photostability, biocompatibility and fluorescent signal NIRF imaging has multi-detection capability and high sensitivity in cancer imaging and therapy [126] Still, new NIR fluorescence imaging dyes have been developed to observe tumors with the enhanced fluorescent signal (IR-783) [127] The targeting theranostic system using NIRF imaging dye (Cy5.5) and anticancer
drug (irinotecan) was also evaluated by Choi et al [128] for therapy
and early diagnosis of colorectal cancer
4 SURFACE ENGINEERING
With a possibility of surface modification, nanoparticles, there-fore, could target and accumulate in a specific tissue [101] Several approaches have been investigated for targeting the colonic cancer region
4.1 Chitosan-Coated Microspheres
The most promising process of surface modification in targeted colorectal cancer is the CS coating on surface of PLGA nanoparti-cles An original PLGA, which has shortage of functional groups on surface, has been suggested to be coated by chitosan for specialized targeting and biomimetic purposes [129] The CS outer shell also facilitated a sustained drug release and an increased stability of macromolecules like proteins, as well as the promotion of cellular adhesion and the retention of the delivery system at the target site [130-132] Generally, CS could be coated on the surface of PLGA nanoparticles by two basic methods so-called physical adsorption
and chemical binding [133] (Fig 8) According to the results of this
research, pH values of CS solution could be modified to regulate the surface charges of nanoparticles and would benefit more affinity
to cancer cells Besides, controlled drug release would be achieved through this system
In addition to the coating process of PLGA nanoparticles, chito-san-coated alginate microparticles containing oxaliplatin were in-vestigated for oral administration for colorectal cancer [134] This research proposed that mucoadhesive microspheres, and particu-larly pH sensitive character could prevent drug release at an acidic environment and deliver the chemotherapeutics to the intestinal site
specifically In vivo data demonstrated that efficient therapeutic
effects in an orthotopic mouse model of colorectal cancer were observed by substantially reduced the tumor burden and reduced mortality
4.2 Enteric Coating
Enteric coating are usually applied for solid dosage forms like tablets and capsules for delayed release formulations [135, 136] In these applications, enteric coating materials should be efficient and safe for controlled drug delivery [137] Various types of aqueous coating suspensions are currently available such as Aquacoat®, Surelease®, Kollicoat®, Eudragit®, Advantia® and Acryl-Eze® with advantages for toxicology and environment [138] For targeting colorectal cancer by polymer-based nanoparticles, Eudragit® S100
is a preferred selection due to its ability of dissolving at pH 7 or higher only [4, 42, 92] Conventional coating pan is generally
ap-plied in the coating process [4, 92] or oil-in-oil solvent evaporation
method [42]
4.3 Ligand Conjugation
Although ligand conjugation has been reported in various types
of nanoparticles for targeting purposes [139-141], there have been only a few reports about targeting colon cancer cells using ligand conjugation in polymer-based nanoparticles Folic acid [44, 90] and hyaluronic acid [91, 92] are the most common targeting ligand in recent research Folate receptors are highly expressed in colorectal and numerous tumors [142-144] Consequently, the utility of folic acid in conjugated nanoparticles as a recognition moiety has been
Trang 6investigated extensively due to its ease of conjugation, high affinity
for the folate receptor and the limited distribution of its receptor in
normal tissues [145, 146] Hyaluronic acid, another ligand
conjuga-tion, possesses a high binding affinity to various cancer cells
(over-expressed CD44) specifically [147-149] Given excellent properties
including nontoxic, nonimmunogenic and particularly versatile
modifications, hyaluronic acid-decorated nanoparticles have been
extensively investigated in cancer therapy [150-152]
CONCLUSION AND FUTURE PERSPECTIVES
Recent advances in polymer-based nanoparticles have indicated
the potential use of polymers in both therapy and diagnosis of
colo-rectal cancer PLGA and CS are popular polymers which have been
most frequently explored Moreover, an increasing number of
in-vestigations on albumin or discovery of new materials demonstrates
the importance of relevant studies in the field Surface engineering
techniques which provide more versatile methods for cell-specific
targeting of nanoparticles have been exploited in an effort to reach a
successful treatment of the cancer In parallel to studies of
opti-mized drug carriers, research towards imaging agents for diagnosis
of precancerous colonic lesions using polymer-based nanoparticles
leads to new key tools for theranostics Although in the past most
research focused on several carrier types loaded with approved
pharmaceutical ingredients for colorectal cancer therapy, an
in-creasing number of studies on smart nano-based systems with new
nanomaterials and potential surface engineering for theranostics
brings an expectation of important beneficiaries of these inventions
in near future
ACKNOWLEDEGMENTS
We would like to thank Institute for Frontier Materials (Deakin
University, Waurn Ponds, Victoria, Australia) and Australian
Gov-ernment for their supports and offering the Endeavour Fellowships
program to Dr Thao Truong-Dinh Tran to undertake study,
re-search and professional development in Australia We also thank
International University, Vietnam National University – Ho Chi
Minh City for their continued, generous supports to our activities
CONFLICT OF INTEREST
The authors confirm that this article content has no conflict of
interest
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The author has requested enhancement of the downloaded file All in-text references underlined in blue are linked to publications on ResearchGate The author has requested enhancement of the downloaded file All in-text references underlined in blue are linked to publications on ResearchGate
...and early diagnosis of colorectal cancer
4 SURFACE ENGINEERING
With a possibility of surface modification, nanoparticles, there-fore, could target and. ..
PLGA-based nanoparticles as cancer drug delivery systems Asian Pac J Cancer Prev 2014; 15: 517-535
[9] Prabaharan M Chitosan-based nanoparticles for tumor-targeted drug delivery Int J Biol Macromol... chitosan-4-thiobutylamidine
con-jugate AAPS PharmSciTech 2010; 11: 1185-92
[75] Sezer AD, Cevher E Topical drug delivery using chitosan
nano -and microparticles Expert Opin Drug