Oral delivery of protein and peptide drugs: from non-specific formulation approaches to intestinal cell targeting strategies

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Theranostics 2022, Vol. 12, Issue 3

https://www.thno.org

1419

Theranostics

2022; 12(3): 1419-1439. doi: 10.7150/thno.61747

Review

Oral delivery of protein and peptide drugs: from

non-specific formulation approaches to intestinal cell

targeting strategies

Guanyu Chen1, Weirong Kang2, Wanqiong Li1, Shaomeng Chen1, Yanfeng Gao1

1. School of Pharmaceutical Sciences (Shenzhen), Sun Yat-sen University, Shenzhen, China.

2. Department of Pharmacology and Pharmacy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China.

 Corresponding author: Prof. Yanfeng Gao, School of Pharmaceutical Sciences (Shenzhen), Sun Yat-sen University, Shenzhen 518107, China. Phone: +86 020

84723750; fax: +86 020 84723750. E-mail: gaoyf29@mail.sysu.edu.cn

See http://ivyspring.com/terms for full terms and conditions.

Received: 2021.04.17; Accepted: 2021.11.20; Published: 2022.01.01

Abstract

The past few years has witnessed a booming market of protein and peptide drugs, owing to their superior

efficiency and biocompatibility. Parenteral route is the most commonly employed method for protein and

peptide drugs administration. However, short plasma half-life protein and peptide drugs requires

repetitive injections and results in poor patient compliance. Oral delivery is a promising alternative but

hindered by harsh gastrointestinal environment and defensive intestinal epithelial barriers. Therefore,

designing suitable oral delivery systems for peptide and protein drugs has been a persistent challenge. This

review summarizes the main challenges for oral protein and peptide drugs delivery and highlights the

advanced formulation strategies to improve their oral bioavailability. More importantly, major intestinal

cell types and available targeting receptors are introduced along with the potential strategies to target

these cell types. We also described the multifunctional biomaterials which can be used to prepare oral

carrier systems as well as to modulate the mucosal immune response. Understanding the emerging

delivery strategies and challenges for protein and peptide drugs will surely inspire the production of

promising oral delivery systems that serves therapeutic needs in clinical settings.

Key words: Protein and peptide drug; Oral delivery system; Physical and biochemical barrier; Intestinal mucosa; Intestinal cell

targeting; Oral bioavailability.

Introduction

Enormous efforts have been made over the past

few decades to realize the therapeutic efficacy of

protein and peptide drugs (PPDs). Owing to their

excellent specificity and biocompatibility, PPDs can

achieve ideal therapeutic effects at relatively low

doses [1]. Since the isolation of insulin in 1922, the use

of PPDs as therapeutic agents has been considered as

an attractive approach to combat various diseases

(Figure 1). Recent developments in the biotechnology

and pharmaceutical sciences have made it possible to

produce potential therapeutic PPDs in commercial

quantities [2]. By far, over 240 PPDs has been

approved by FDA and a variety of potential drug

candidates in clinical trials.

Though parenteral administration is the most

commonly employed administration route for PPDs,

it often associates with poor patient compliance [3].

Compared to parental administration, oral drug

delivery routes are advantageous in terms of patient

compliance, safety, long-term dosing and

manufacturing costs. Further, oral administration is

used for both local and systemic delivery of a wide

range of drug molecules, from small molecules to

biomacromolecules [4]. However, oral delivery of

macromolecules (such as PPDs) is particularly

challenging due to their physicochemical properties

and the involving barriers in the gastrointestinal tract

(GIT) [5]. The major strategies to deliver PPDs orally

Ivyspring

International Publisher

Theranostics 2022, Vol. 12, Issue 3

https://www.thno.org

1420

with improved the therapeutic efficacy can be

categorized into non-targeting and targeting delivery,

including chemical modification and drug delivery

systems for PPDs to avoid enzymatic degradation and

reduce off-target drug distribution. Targeting

different GIT area can be achieved by exploiting its

physiological features and combining the PPDs with

suitable drug formulations [6]. Moreover, the

presence of numerous types of intestinal cells, such as

enterocytes, M cells, goblet cells and Paneth cells

interspersed throughout the GIT provides various

targets and allows for the design of a broad array of

passive or active targeting delivery systems.

In this review, we summarize major barriers for

oral delivery of PPDs, and the state-of-the-art

formulation approaches for promoting the oral

bioavailability of PPDs. Intestinal cell targeting

strategies are presented with an emphasis on

examples that showed great potential for clinical

applications. Additionally, multifunctional

biomaterials which can be used to prepare oral carrier

systems as well as to modulate the mucosal immune

response are also discussed.

Physical and biochemical barriers and

mechanism of intestinal drug absorption

The absorption of orally administered PPDs

from the GIT into the systemic circulation is limited

by various factors. These include the release of drugs

from the carrier systems and pass on their way to the

target receptors within the harsh intestinal

environment. Ingested PPDs first encounter digestive

enzymes in our oral cavity, including amylase and

lipase in the saliva [7]. The second enzymatic barrier is

the intensive acidic environment and the presence of

pepsin and cathepsin that degrades most of the PPDs

in our stomach [8]. Gastric pH might alter the

ionization of the PPDs causing change of structure or

function of the drug. Moreover, trypsin and

α-chymotrypsin are the major proteolytic enzymes in

the intestinal lumen [9].

Figure 2 shows the mucus layer covering GIT

epithelial membrane is considered as the first physical

barrier. Mucin is the main component which is a

highly glucosylated glycoprotein. The backbone

consists repeating sequences of serine, proline and

threonine residues. The O-linked oligosaccharide side

chains are generally terminated in L- fructose,

sulfonic acid or sialic acid. Therefore, the intestinal

mucus layer shows negatively charged [10, 11].

Second physical barrier, the layer of epithelial cells

connecting with tight junctions, which forming a seal

wall for the drug permeation [12]. Furthermore, PPDs

being metabolized by the enterocytes cytochrome

P450 3A4 (CYP3A4) enzyme and being pumped out

via P-gp efflux protein, as well as the post-absorptive

clearance are other involving barriers for oral drug

delivery [13].

Figure 1. Milestones in the development of oral delivery of PPDs.

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