Nanotechnology Community

What are the primary physiological and biochemical barriers to the oral bioavailability of nanoformulated drugs, and how can surface modifications or functionalization strategies be optimized to enhance mucosal uptake and systemic absorption?

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Kabirat Babalola
Ph.D Student
The University of Alabama
Tuscaloosa AL
[email protected]

Disclaimer: Opinions expressed are solely my own and do not express the views or opinions of my employer.
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Hi Kabirat,
This illustration from Zhu et al (Zhu, Q., et al. (2021). Acta Pharmaceutica Sinica B 11(8): 2416-2448) summarizes the barriers for the formulation to overcome within the GIT: 
Surface modification and/or functionalization can help with traversing the mucus barrier, targeting specific cells within the GIT and could mediate paracellular transport.

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Kanika Suri
Scientist
Millennium: The Takeda Oncology Company
Cambridge MA
[email protected]

Disclaimer: Opinions expressed are solely my own and do not express the views or opinions of my employer.
------------------------------

Original Message:
Sent: 03-14-2025 20:49
From: Kabirat Babalola
Subject: Question about orally delivered nanoformulated drugs

What are the primary physiological and biochemical barriers to the oral bioavailability of nanoformulated drugs, and how can surface modifications or functionalization strategies be optimized to enhance mucosal uptake and systemic absorption?

------------------------------
Kabirat Babalola
Ph.D Student
The University of Alabama
Tuscaloosa AL
[email protected]

Disclaimer: Opinions expressed are solely my own and do not express the views or opinions of my employer.
------------------------------

Hi Suri, thanks a lot for your response and thank you for citing your reference. I will read the paper. 

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Kabirat Babalola
Ph.D Student
The University of Alabama
Tuscaloosa AL
[email protected]

Disclaimer: Opinions expressed are solely my own and do not express the views or opinions of my employer.
------------------------------

Original Message:
Sent: 03-17-2025 09:27
From: Kanika Suri
Subject: Question about orally delivered nanoformulated drugs

Hi Kabirat,
This illustration from Zhu et al (Zhu, Q., et al. (2021). Acta Pharmaceutica Sinica B 11(8): 2416-2448) summarizes the barriers for the formulation to overcome within the GIT: 
Surface modification and/or functionalization can help with traversing the mucus barrier, targeting specific cells within the GIT and could mediate paracellular transport.

------------------------------
Kanika Suri
Scientist
Millennium: The Takeda Oncology Company
Cambridge MA
[email protected]

Disclaimer: Opinions expressed are solely my own and do not express the views or opinions of my employer.

Original Message:
Sent: 03-14-2025 20:49
From: Kabirat Babalola
Subject: Question about orally delivered nanoformulated drugs

What are the primary physiological and biochemical barriers to the oral bioavailability of nanoformulated drugs, and how can surface modifications or functionalization strategies be optimized to enhance mucosal uptake and systemic absorption?

------------------------------
Kabirat Babalola
Ph.D Student
The University of Alabama
Tuscaloosa AL
[email protected]

Disclaimer: Opinions expressed are solely my own and do not express the views or opinions of my employer.
------------------------------

Hi Kabirat,

Thank you for the important question.  My response is a little longer as the topic is vast. 

Many barriers exist for oral nanoparticles (NP), e.g., the harsh environment of the stomach (pH, enzymes, etc.), intestinal absorption limitations (enzymes, bile, mucosa, etc.), and GI transit. 

Surface functionalization to target specific receptors (e.g. transferrin, folic acid receptors, etc.) or GI site (e.g., targeted delivery in colon cancer and inflammatory bowel diseases, IBD) will improve bioavailability and therapeutic efficacy. Some approaches for IBD may be redox NPs with e.g, catalase to specifically accumulate in the inflamed colon or with ligands e.g., folic acid to target inflamed tissue in colitis.

Challenges for oral NPs for targeted delivery outside the GIT are that NPs must penetrate the mucus gel, traverse the GI epithelial cells lining, and then the endothelial cells of blood vessels. Endosomal escape is important for both transcytosis of the nanocarriers.

Functionalization with proteolytic enzymes like papain can increase mucosal penetration. Surface modification with the Fc part of IgG, B₁₂, metformin, etc. can increase endosomal escaping and exocytosis.

 

To reach distant parts of the body, macrophages and dendritic cells in the gut-associated lymphatic tissue can be targeted. The NPs undergo transcytosis at Peyer's patches by Microfold (M) cells and are then transported by macrophages to the systemic circulation. 1,3-D glucan, RGD, etc. can target the M cells of the Peyer's patch. For oral vaccines, functionalization with mannose, lectins (WGA), etc. can target the APCs in Peyer's patches.

 

I hope others will provide their opinion.

Delwar

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Muhammad Hussain Ph.D.
Professor of Pharmaceutics
University of Maryland Eastern Shore
Princess Anne MD
[email protected]

Disclaimer: Opinions expressed are solely my own and do not express the views or opinions of my employer.
------------------------------

Original Message:
Sent: 03-14-2025 20:49
From: Kabirat Babalola
Subject: Question about orally delivered nanoformulated drugs

What are the primary physiological and biochemical barriers to the oral bioavailability of nanoformulated drugs, and how can surface modifications or functionalization strategies be optimized to enhance mucosal uptake and systemic absorption?

------------------------------
Kabirat Babalola
Ph.D Student
The University of Alabama
Tuscaloosa AL
[email protected]

Disclaimer: Opinions expressed are solely my own and do not express the views or opinions of my employer.
------------------------------

Thank you very much for the detailed response, Dr. Hussain. 

------------------------------
Kabirat Babalola
Ph.D Student
The University of Alabama
Tuscaloosa AL
[email protected]

Disclaimer: Opinions expressed are solely my own and do not express the views or opinions of my employer.
------------------------------

Original Message:
Sent: 03-19-2025 23:01
From: Muhammad Hussain
Subject: Question about orally delivered nanoformulated drugs

Hi Kabirat,

Thank you for the important question.  My response is a little longer as the topic is vast. 

Many barriers exist for oral nanoparticles (NP), e.g., the harsh environment of the stomach (pH, enzymes, etc.), intestinal absorption limitations (enzymes, bile, mucosa, etc.), and GI transit. 

Surface functionalization to target specific receptors (e.g. transferrin, folic acid receptors, etc.) or GI site (e.g., targeted delivery in colon cancer and inflammatory bowel diseases, IBD) will improve bioavailability and therapeutic efficacy. Some approaches for IBD may be redox NPs with e.g, catalase to specifically accumulate in the inflamed colon or with ligands e.g., folic acid to target inflamed tissue in colitis.

Challenges for oral NPs for targeted delivery outside the GIT are that NPs must penetrate the mucus gel, traverse the GI epithelial cells lining, and then the endothelial cells of blood vessels. Endosomal escape is important for both transcytosis of the nanocarriers.

Functionalization with proteolytic enzymes like papain can increase mucosal penetration. Surface modification with the Fc part of IgG, B₁₂, metformin, etc. can increase endosomal escaping and exocytosis.

 

To reach distant parts of the body, macrophages and dendritic cells in the gut-associated lymphatic tissue can be targeted. The NPs undergo transcytosis at Peyer's patches by Microfold (M) cells and are then transported by macrophages to the systemic circulation. 1,3-D glucan, RGD, etc. can target the M cells of the Peyer's patch. For oral vaccines, functionalization with mannose, lectins (WGA), etc. can target the APCs in Peyer's patches.

 

I hope others will provide their opinion.

Delwar

------------------------------
Muhammad Hussain Ph.D.
Professor of Pharmaceutics
University of Maryland Eastern Shore
Princess Anne MD
[email protected]

Disclaimer: Opinions expressed are solely my own and do not express the views or opinions of my employer.

Original Message:
Sent: 03-14-2025 20:49
From: Kabirat Babalola
Subject: Question about orally delivered nanoformulated drugs

What are the primary physiological and biochemical barriers to the oral bioavailability of nanoformulated drugs, and how can surface modifications or functionalization strategies be optimized to enhance mucosal uptake and systemic absorption?

------------------------------
Kabirat Babalola
Ph.D Student
The University of Alabama
Tuscaloosa AL
[email protected]

Disclaimer: Opinions expressed are solely my own and do not express the views or opinions of my employer.
------------------------------

Hi Kabirat,

Kanika and Delwar have provided a very thorough summarization of the barriers to the oral bioavailability of nanomedicines, so I will mostly focus on surface modification strategy. 

PEGylation is the gold standard in the filed to improve particle distribution across the mucosa and enhance delivery to the underlying epithelium.  It is essential for drug carrier nanoparticles to first diffuse through the viscoelastic mucus layer. Given that mucus can pose both steric and adhesive barrier properties, any mucus-penetrating particle system must be sufficiently small to evade steric obstruction by the dense network of mucin fibers and sufficiently muco-inert to evade association to mucins. 

Here is an illustration from a publication that summarize the important features for enhanced muco-penetration.

 If you want to read more, I recommend this review article: https://www.sciencedirect.com/science/article/pii/S0169409X17301813#s0045

------------------------------
Fan Zhang Ph.D.
Assistant Professor
University of Florida
Gainesville FL
[email protected]

Disclaimer: Opinions expressed are solely my own and do not express the views or opinions of my employer.
------------------------------

Original Message:
Sent: 03-14-2025 20:49
From: Kabirat Babalola
Subject: Question about orally delivered nanoformulated drugs

What are the primary physiological and biochemical barriers to the oral bioavailability of nanoformulated drugs, and how can surface modifications or functionalization strategies be optimized to enhance mucosal uptake and systemic absorption?

------------------------------
Kabirat Babalola
Ph.D Student
The University of Alabama
Tuscaloosa AL
[email protected]

Disclaimer: Opinions expressed are solely my own and do not express the views or opinions of my employer.
------------------------------