//Background//---
The
concept of cancer nanomedicine has made in the 1970s and 80s. From this period,
it was known that tumor tissue tends to be accumulated the molecule including
the drug, because the (vascular) tissue around the tumor is leaky, meaning the
high permeability. This high-retention effect of the molecule is called “the
enhanced permeability and retention(EPR) effect”(2,3).
The
multi-phase understanding of the cancer cell, such as material properties,
genetic/molecular/metabolic hallmarks, enables us to realize the targeted
therapy against the tumor through following things.
*Specific receptors(4-7)
*pH, temperature(6)
*Thermotherapy(8)
*Theranostic(Imaging and diagnostic
development)(8,9)
Through
these developments, cancer nanomedicine is expected to on-demand delivery with
exquisite anatomical/tissue’s/cellular specificity, in which additional
cytotoxic and diagnostic development could be realized.
However, the current development of analysis on
the interaction of nano-particles and biology in vivo clearly indicates opacity
for the smooth journey to significant success of targeted cancer therapy by the
nano-formulated drug.
Irene
de Lázaro & David J. Mooney belonging to Harvard University, the United
States of America review about obstacles and opportunities of cancer
nanomedicine in order to make Engineering and Applied Science go forward(1). I
hope to share summery of these contents with the global important readers.
//Clinical status(1)//---
*Only 14 systemically administered cancer
nanomedicine have been approved worldwide from 1993 to 2019, many of which are
liposomal nanocarrier and chemotherapy including the refractory cancer-type
such as advanced/metastatic cancer(See Table.1). However only a small part of
the formulation is more effective than the normal parent-free drugs. No
actively targeted or stimulus-responsive cancer nanomedicine hasn’t yet been
approved, but more than 50 anti-cancer clinical trial is underway(10).
//Challenging matters(1)//---
(Nano–bio interactions in the blood)
*Forming a corona on the surface of
nanoparticle, which alters physicochemical characteristics, such as surface
charge / chemistry / hydrodynamic size / immunogenicity / off-target cell
interaction(11-13). These alteration affects interaction with blood cells, such
as phagocytes, erythrocytes, platelets. These interaction partly determines the
biodistribution and clearance(14,15).
---
(Sequestration in organs of the mononuclear
phagocyte system)
*Sequestration by the spleen and liver
before nanoparticles are delivered in the tumor lesion(16,17).
*Opsonization, which is the effect that the
adhesives like protein, amino acid on the nanoparticles makes the phagocytosis
enhance. Therefore, a corona could reduce drug delivery efficiency, and may
lead to chronic toxicity due to non-biodegradable nanoparticles, altering
metabolism(18).
---
(Tumor extravasation)
*High interstitial pressure due to vascular
hyperpermeability hinders nanoparticles from extravasation into the tumor
microenvironment(19).
*Cancer heterogeneity could indicate
uncertainty of leaky vasculature(20), and understanding of the tumor vascular
barrier remains open(21).
---
(Intra-tumor distribution)
*Deep and uniform nanoparticle drug
penetration is challenging, especially denser stroma in the solid tumor(19,22).
*Size and shape dependent steric
effects(23,24)((1) See Fig.2a)
*Barrier of parenchyma region, such as
intricate and high density of extracellular matrix(ECM) proteins(25),
sequestration by stromal cells(26,27).
---
(Intracellular uptake, trafficking and
cargo release)
*The degradation of nano-cargo before
efficient drug release(28).
---
(Complexity of preclinical design)
The reproducible and cumulative research is
challenging in the following reasons.
*Inconsistent physicochemical and
biological characterization of nanoparticles.
*Lack of direct, side-by-side comparison of
each nanoparticle.
*Few reporting of experimental condition.
*A paucity of quantitative data.
*Clear guidelines is not yet set by The
Minimum Information Reporting in Bio–Nano Experimental Literature (MIRIBEL)
guidelines(40). Therefore, research collaboration is much needed. A large
research project and clinical design are highly demanding for combating above
challenging matters.
//Opportunities//---
(Special note)
*Re-engineering cancer nanomedicine to
prevent undesired interaction in the delivery way to the tumor. A deeper
understanding of nano-bio interactions.
*Creative diagnostic and therapeutic
applications of nanomedicine
---
(Tumor accumulation beyond the EPR effect)
*Transcytosis could be harnessed to improve
nanoparticle adhesion to the tumor(21), which mean the improvement of mobility
capability in the tissue even in many barriers. For example, albumin binds to
receptor in endothelial cells, which can make transcytosis, and have
extravasation from the vascular system to the tumor. Therefore, albumin
proteins are bound to the anti-cancer drugs(29,30). Other example: iRGD
(CRGDK/RGPD/EC)- a neuropilin-1 (NRP1)-dependent transcytosis(31).
---
(Considering the entire delivery flow)
*Anti-fouling hydrophilic polymers such as
polyethylene glycol(PEG) avoid opsonization/formation of corona on the
nanoparticles could prevent alteration of physicochemical properties(32).
*The trade-off between interstitial
pressure and vascular leakiness. In this notion, we could harness this pressure
(forward direction) to deliver nanoparticles.
*Cytokine and chemokine dependent cancer
tropism could be utilized.
---
(Computational contribution)
*Large nanoparticle library access.
*Artificial intelligence, big data .
There two resource enables us to establish
fundamental relationships between nanoparticle properties and biological
outcome prediction, such as biodistribution, uptake ability(33-35).
*Database of gene functions between gene
and (glycol)protein for proper formation of surface protein
---
(Harnessing the protein corona(1))
*Corona multi-omics analysis statistically
and/or each patients enable us to design and stimulates the immune function via
antigen presentation, recognition and immune cell priming(See Fig.3a). We could
redesign nanoparticle with low-affinity against detected corona. Therefore,
corona information from the liquid biopsy (blood) is important to redesign.
*Diagnosis: The nanoparticle injection for
targeting lesion for the disease-specific corona analysis.
*The adsorption of tumor antigen as corona
on the nanoparticle could enhance the abscopal effect for distant metastatic
cancer in a combination manner of radio or phototherapy(36,37).
---
(Stimulation tumor specific immune
function)
*Sequestration of nanoparticle in the
immune cell in the blood could alter immune function to a cancer-specific trait
as following.
1: Carbon nanotube included monocyte
accumulates in preferably cancer cell(38).
2: Neutrophil taking up nanoparticle is
facilitated to deliver cancer sites(39).
*Immune function mediated durable
anti-cancer response including off-site reaction, such as in blood, lymphatic
system, and on-site reaction such as tumor microenvironment.
To harness immune system in a manner
positive to cancer treatment, the nano-immune interaction needs to be
scrutinized in vitro / in vivo in both human and mammalian cells before
clinical adaptation. On the other perspective, we need to carefully analyze
immunogenicity in the therapy based on the nanoparticles drug in the clinical
case.
//The cell-specific delivery system//---
Why
does SARS-CoV-2 virus maintain ACE2-binding ability even in nano-bio
interaction? One reason may be the large viral road, meaning statistical
advantage. The other reason may be delivery route from oral/nasal cavity to
respiratory system, so the liquid-like interaction is small and there is much
space for distribution. Another reason may be the material component of surface
S-protein for recognition of ACE2. S-protein includes sugar(glycol-protein),
which is hydrophilic. Therefore, the portion of sugar protects formation of
corona and the protein binding site(epitope) from the surrounding materials.
From
this discussion, we can get cogitations for the cell-specific delivery system.
We could use the virus as a carrier. We need to consider the structure and component
of surface proteins having epitope with target cell.
The
important perspective by Irene de Lázaro & David J. Mooney is to enhance
transcytosis. Actually, there are a lot of anatomical barriers from injection
cite to the lesion. Therefore, transcytosis through barrier(cell) is one of
requirement for the nanoparticle-based drug delivery system.
The
nanoparticle specific to the target lesion via the carefully designed surface
proteins could be harnessed to the detailed diagnosis through the on-site and
specific disease specific proteins and amino acid from the corona adhesives.
//Concluding remarks(1)//---
There
are a lot of barriers for the cancer nanomedicine more than initially expected.
However, we don’t need to be disappointed with this complex matters. If we ccan
change this challenging matters to opportunities, we can provide nanomedicine
from bench to “bedside” of many patients needing state-of-the-art therapy with
refractory diseases in a accelerated fashion.
//Contributions(1)//---
I.d.L. and D.J.M. conceived and wrote the
manuscript.
(Reference)
(1)
Irene de Lázaro & David J. Mooney
Obstacles and opportunities in a forward
vision for cancer nanomedicine
Nature Materials (2021)
---
Author information
Affiliations
John A. Paulson School of Engineering and
Applied Sciences, Harvard University, Cambridge, MA, USA
Irene de Lázaro & David J. Mooney
Wyss Institute for Biologically Inspired
Engineering at Harvard University, Boston, MA, USA
Irene de Lázaro & David J. Mooney
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