Mucoadhesive chitosan microcapsules for controlled gastrointestinal delivery and oral bioavailability enhancement of low molecular weight peptides

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Journal of Controlled Release 365 (2024) 422–434

Available online 30 November 2023

Mucoadhesive chitosan microcapsules for controlled gastrointestinal

delivery and oral bioavailability enhancement of low molecular

weight peptides

Kyungjik Yang

, Hwa Seung Han

, Seung Hwan An

, Kyung Hoon Park

, Keonwook Nam

Shinha Hwang

, Yuyeon Lee

, Sung Yeon Cho

, Taehyung Kim

, Deokyeong Choe

Sang Won Kim

, Wonkyu Yu

, Hyunah Lee

, Jiyong Park

, SangGuan You

, Dong-

Gyu Jo

, Ki Young Choi

, Young Hoon Roh

***

, Jae Hyung Park

****

Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, 50 Yonsei-ro, Seodaemun-gu, Seoul 03722, Republic of Korea

Graduate Program in Bioindustrial Engineering, College of Life Science and Biotechnology, Yonsei University, 50 Yonsei-ro, Seodaemun-gu, Seoul 03722, Republic of

Korea

Department of Marine Food Science and Technology, Gangneung-Wonju National University, Gangneung 120, Republic of Korea

School of Food Science and Biotechnology, College of Agriculture and Life Sciences, Kyungpook National University, Daegu 41566, Republic of Korea

Yonsei University Dairy R&D Center, Asan, Republic of Korea

Department of Bio-Convergence Engineering, Dongyang Mirae University, 445-8, Gyeongin-ro, Guro-gu, Seoul 02841, Republic of Korea

Nutrex Technology, 670 Daewangpangyo-ro, Seongnam 13494, Republic of Korea

School of Pharmacy, Sungkyunkwan University, Suwon 16419, Republic of Korea

Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul 06351, Republic of Korea

Biomedical Institute for Convergence at SKKU (BICS), Sungkyunkwan University, Suwon 16419, Republic of Korea

East Coast Research Institute of Life Science, Gangneung-Wonju National University, 120 Gangneung, Gangwon 210-702, Republic of Korea

School of Chemical Engineering, Sungkyunkwan University, Suwon 16419, Republic of Korea

ARTICLE INFO

Keywords:

Collagen peptide

Chitosan

Microcapsule

Phytic acid

Controlled gastrointestinal delivery

Oral bioavailability

ABSTRACT

A bioactive compound, collagen peptide (CP), is widely used for biological activities such as anti-photoaging and

antioxidant effects, with increased oral bioavailability because of its low molecular weight and high hydrophi-

licity. However, controlling release time and increasing retention time in the digestive tract for a more conve-

nient oral administration is still a challenge. We developed CP-loaded chitosan (CS) microcapsules via strong and

rapid ionic gelation using a highly negative phytic acid (PA) crosslinker. The platform enhanced the oral

bioavailability of CP with controlled gastrointestinal delivery by utilizing the mucoadhesiveness and tight

junction-opening properties of CS. CS and CP concentrations varied from 1.5 to 3.5% and 0–30%, respectively,

for optimal and stable microcapsule synthesis. The physicochemical properties, in vitro release prole with in-

testinal permeability, in vivo oral bioavailability, in vivo biodistribution, anti-photoaging effect, and antioxidant

effect of optimized CS microcapsules were analyzed to investigate the impact of controlling parameters. The

structure of CS microcapsules was tuned by PA diffused gradient ionic cross-linking degree, resulting in a

controlled CP release region in the gastrointestinal tract. The optimized microcapsules increased C

max

, AUC, and

max

by 1.5-, 3.4-, and 8.0-fold, respectively. Furthermore, CP in microcapsules showed anti-photoaging effects by

downregulating matrix metalloproteinases-1 via antioxidant effects. According to our knowledge, this is the rst

study to microencapsulate CP for oral bioavailability enhancement. The peptide delivery method employed is

simple, economical, and can be applied to customize bioactive compound administration.

* Correspondence to: D-G Jo, School of Pharmacy, Sungkyunkwan University, Suwon 16419, Republic of Korea.

** Correspondence to: K Y Choi, Department of Marine Food Science and Technology, Gangneung-Wonju National University, Gangneung 120, Republic of Korea.

*** Correspondence to: Y H Roh, Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, 50 Yonsei-ro, Seodaemun-gu, Seoul

03722, Republic of Korea.

**** Correspondence to: J H Park, School of Chemical Engineering, Sungkyunkwan University, Suwon 16419, Republic of Korea.

E-mail addresses: jodg@skku.edu (D.-G. Jo), kiyoungchoi7@gmail.com (K.Y. Choi), yr36@yonsei.ac.kr (Y.H. Roh), jhpark1@skku.edu (J.H. Park).

These authors contributed equally to this work.

Contents lists available at ScienceDirect

Journal of Controlled Release

journal homepage: www.elsevier.com/locate/jconrel

https://doi.org/10.1016/j.jconrel.2023.10.021

Received 28 February 2023; Received in revised form 21 August 2023; Accepted 16 October 2023

Journal of Controlled Release 365 (2024) 422–434

423

1. Introduction

Microencapsulation strategies of bioactive compounds have been

studied to increase the loading capacity (LC), stability in the digestive

environment, and controlled release in the gastrointestinal tract. Phys-

ical, physicochemical, and chemical methods have developed micro-

capsules with core-shell, layer-by-layer, and multicompartmental

structures [1–4]. Ionic gelation is one of the preferred physicochemical

microencapsulation techniques, performed by cross-linking of diverse

polyelectrolytes, such as alginate, gelatin, and chitosan (CS), and

multivalent ions, such as Ca

and HPO

2−

[5–9]. Particularly, ion-

induced CS microcapsule formation has been applied for the oral de-

livery of several bioactive compounds, including antioxidants, vitamins,

and probiotics, as positively charged CS biomaterial has high biocom-

patibility, good mucoadhesiveness via electrostatic interaction, and tight

junction-opening properties via interaction with tight junction proteins

[10–13]. Moreover, the release kinetics of bioactive compounds from CS

microcapsules were controlled by the physicochemical properties of

microcapsules, such as size, morphology, structure, and porosity.

However, CS microencapsulation of ultra-low-molecular-weight and

highly hydrophilic bioactive compounds suffer from low encapsulation

efciency (EE), diffusional loss during storage, and poorly controlled

release in the gastrointestinal tract, leading to the cargo being quickly

diffused out through a porous matrix [14–16].

Recently, we encapsulated a nucleic acid, protein, and probiotics into

CS microcapsules with improved EE, digestive stability, controlled

gastrointestinal release, and oral bioavailability by adopting the strong

cross-linking agent phytic acid (PA) [17–20]. PA, also known as an

inositol hexakisphosphate, is a natural product in grains and legumes

with varied bioactivities, disease prevention effects, and chelating

abilities [21–23]. PA has relatively larger ionic strength than sodium

tripolyphosphate, the most used cross-linking agent for CS, owing to its

six phosphate groups with strong negative charges. Moreover, nucleic

acid nanoparticles were loaded into CS microcapsules cross-linked with

PA, forming multi-compartmental structures that showed tunable

loading patterns, enhanced biostability, sustained release of bioactive

materials, organ-specic delivery efciency, and bioavailability in the

digestive environment [19,24,25]. Although strong and rapid cross-

linking of CS and PA showed successful microencapsulation, the car-

gos were limited to probiotics or bioactive materials with relatively

large molecular weight or charge density.

Various bioactive compounds, such as peptides, polyphenols, avo-

noids, anthocyanin, non-starch polysaccharides, and natural marine

products, have been studied to develop protective agents against ultra-

violet B (UVB)-induced photoaging [26–28]. These compounds exert

anti-photoaging effects by attenuating reactive oxygen species produc-

tion, downregulating matrix metalloproteinases (MMP) expression, and

upregulating hyaluronan synthase [29,30]. Among these compounds,

low molecular weight collagen peptide (CP) has recently generated

signicant interest from researchers because of its anti-photoaging ef-

fects, water solubility, biocompatibility, and cost-effectiveness [31]. CP

is a collagen hydrolysate made from collagen proteins through acidic,

alkaline, or enzymatic hydrolysis; it comprises a few amino acids

(glycine, proline, and hydroxyproline) with low molecular weight,

approximately 1 kDa [32]. Low-molecular-weight and highly hydro-

philic CP can be applied as oral supplementation due to high oral

bioavailability via uptake through oligotransporters in the small intes-

tine and better anti-photoaging effects owing to higher amino acid

accessibility, resulting in high plasma CP concentration, skin tissue

accumulation, and anti-photoaging effects [33–39]. Furthermore, oral

CP administration can be delivered into the dermis more efciently by

systemic circulation; hence, combined oral and topical administration

has shown a more pronounced anti-aging effect [40,41]. Although the

oral bioavailability of CP was considerably increased, it has short

retention time in the gastrointestinal tract as it needs more frequent

administration for more effectiveness.

In this study, CP-loaded CS microcapsules (CP-CS microcapsules)

were prepared for controlled gastrointestinal delivery and enhancement

of oral bioavailability of low-molecular-weight CP. The CP-CS micro-

capsules were synthesized by dripping CP-loaded CS solution via elec-

trostatic extrusion into PA solution and curing with gentle agitation for

stable diffusion-based cross-linking (Fig. 1). The strong and rapid ionic

cross-linking of CS with PA efciently and easily encapsulated low-

molecular-weight CP with high hydrophilicity. The CS and CP concen-

trations, as well as the concentration and pH of PA, varied to obtain the

optimal structural stability of microcapsule and high CP EE. The

morphology, structure, loading pattern, and physicochemical properties

of optimized CP-CS microcapsules were characterized to investigate the

effects of cross-linking degree by different CS concentrations. Addi-

tionally, sustained release of CP in digestive conditions, in vitro intestinal

permeability, in vivo oral bioavailability, in vivo biodistribution, anti-

photoaging effect, and antioxidant effect of CP-CS microcapsules were

analyzed to investigate the gastrointestinal delivery efcacy of orally

administered CP.

2. Materials and methods

2.1. Materials

CS (degree of deacetylation =95%) was purchased from Biotech Co.,

Ltd. (Mokpo, Korea). PA (40% w/w solution in H

O) was obtained from

MSC Co., Ltd. (Yangsan, Korea). CP (molecular weight ≤1 kDa) was

purchased from Geltech (Busan, Korea). Fluorescein isothiocyanate

(FITC), dimethyl sulfoxide, and Hanks’ Balanced Salt Solution (HBSS)

were purchased from Sigma-Aldrich (St. Louis, MO, USA).

2.2. Preparation of CP-CS microcapsules

CP-CS microcapsules were prepared by cross-linking between CS and

PA using the electrostatic extrusion method, as previously described,

with minor modications [20]. The CS solution [1.5–3.5% (w/v)] was

dissolved in diluted vinegar (6.0% acetic acid) in a ratio of 1:6 under

magnetic stirring (300 rpm) for 12 h at 25 ◦C. To CS solutions, 0–30%

(w/v) CP was added and mixed under magnetic stirring (300 rpm) for 3

h at 25 ◦C. A 4% (w/w) PA solution (pH 3.0) was prepared by diluting a

50% (w/w) PA solution with distilled water and adjusting the pH by

adding trisodium citrate. The CP-loaded CS solution was added dropwise

to the PA solution through a 24-G needle using an encapsulator (VAR

V1; Nisco Engineering AG, Zurich, Switzerland). The electrical potential

system was created with a voltage supply and two electrodes (one in the

nozzle and one in the PA solution). The CP-loaded CS solution (0.5 mL)

was allowed to drip at a ow rate of 100

L/min into 20 mL PA solution

with gentle agitation, and the applied voltage was adjusted to 10 kV.

Lastly, the microcapsules were cured in the PA solution, stirred for 1 h at

200 rpm, and washed with distilled water.

2.3. Encapsulation efciency of CP-CS microcapsules

The EE of CP was determined by the entrapped amount of CP in CP-

CS microcapsules. The entrapped CP was indirectly quantied based on

the difference between the total CP in the batch and the unloaded CP in

the external PA solution, as previously reported, with slight modica-

tion (Kim et al., 2020). A standard curve of CP in 1% (w/w) PA solution

(pH 3.0) was obtained to eliminate interference of PA (Fig. S1A). To

calculate the unloaded CP, 10

L solution was extracted from the

external PA solution, diluted by 4-fold with distilled water, and quan-

tied via UV/VIS at 230 nm. The EE was calculated as follows:

Encapsulation efficiency (EE) = (Wtotal CP −Wunloaded CP

Wtotal CP )×100 (1)

where, Wtotal CP is the total weight of CP used for CP-CS microcapsule

K. Yang et al.

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