INTRODUCTION
One of the deadliest malignant tumours, Pancreatic Ductal Adenocarcinoma (PDAC), has an
extremely poor prognosis due to the later stage detection, when surgical resection is no longer
an option. As an alternative, conventional gene therapy offers potentials to safely inhibit
pancreatic cancer progression, but sadly has had only patchy success up to this point. This type
of gene therapy works by putting pancreatic cancer cells into an inactive state and preventing
their proliferation and metastasis. (Bisht et al., 2016; Yu et al., 2020; Zhu et al., 2019)The
majority of patients have already entered the terminal stage before diagnosis because of the
disease's early, obscure, and peculiar symptoms as well as its concealed location.
Extracellular matrix (ECM) deposition that is excessive in Pancreatic Ductal Adenocarcinoma
(PDAC) substantially restricts the ability of therapeutic drugs to penetrate tumours and is linked
to a poor prognosis. The most prominent matrix protein in the tumor's extracellular matrix
(ECM) is collagen, and it is this barrier that makes it so difficult to spread chemotherapeutic
medications or nanomedicines. The immune-suppressive tumour microenvironment
significantly reduces the therapeutic effect of chemotherapy drugs like gemcitabine against
pancreatic cancer. Exosomes, which have an external endocytic vesicle diameter of about 100
nm, are crucial for cell communication. In fact, it has been suggested that they be used to
diagnose and keep track of a variety of disorders (such as Parkinson, Alzheimer, diabetes,
cardiac damage, infection diseases or cancer). It may prove to be a successful technique to
increase the efficacy of chemotherapy by targeting tumor-associated macrophage and
reprogramming the tumour microenvironment.
Nowadays, serological and imaging tests are the mainstays of PDAC diagnosis. The early
identification of PDAC is extremely difficult because serum testing cannot pinpoint particular
tumour areas and each imaging method has limitations of its own. Hence, developing novel
methods for the precise and early diagnosis of PDAC is crucial.
RESEARCHES AND TECHNOLOGIES TO IMPROVE PDAC AND CANCER
CONDITIONS
1) Oridonin-Loaded And GPC1-Targeted Gold Nanoparticles
With the help of hyaluronic acid (HA), anti-Glypican-1 (anti-GPC1) antibody, oridonin (ORI),
gadolinium (Gd), and Cy7 dye, a nanoparticle (NP) based on gold nanocages (AuNCs) was
created. A potential theranostic platform called ORI-GPC1-NP allows for the rapid diagnosis
and efficient treatment of pancreatic cancer. The most popular AuNPs for pancreatic cancer
tomography, ultrasound imaging, NIRF, and MR are oridonin-loaded and GPC1-targeted
AuNPs. The therapeutic potential of magnetic resonance imaging (MRI) and near-infrared
fluorescence (NIRF) was examined in vitro and in vivo. (Qiu et al., 2018)Long-term stability
and fluorescent/MRI properties were shown for ORI-GPC1-NPs. In vitro, pancreatic cancer
cells were drastically reduced in viability and increased in apoptosis by ORI-GPC1-NPs. Blood
testing further indicated that ORI-GPC1-NPs exhibited low toxicity. ORI-GPC1-NPs enabled
multimodal imaging and targeted therapy in pancreatic tumour xenografted mice, according to
in vivo investigations. In this study, we effectively created hollow AuNCs with Gd and Cy7
hybrid-functionalized anti-GPC1 antibodies loaded with ORI (ORI-GPC1-NPs). Good
biocompatibility, the potential for multimodal imaging, regulated drug release, tumor-targeting
efficacy, low toxicity, and high bioavailability are just a few of the beneficial characteristics of
ORI-GPC1-NPs. Poor uptake prevents the majority of NP from reaching tumour tissue. The
nonspecific protein binding and reticuloendothelial system clearance of NPs are factors in their
potential. The potential discrepancies between these NPs could be an indication that ORI, Cy7,
Gd, and anti-GPC1 antibody were successfully bound to AuNCs. The cellular absorption of
the GPC1-targeted NPs (ORI-GPC1-NPs) was substantially higher than that of the non-
targeted NPs (ORI-NPs). In vitro tests for MTT, apoptosis, cell cycle, and migration all
demonstrated surprisingly effective therapeutic results. Antigen-antibody mediated
endocytosis may be the cause of ORI-GPC1-NPs' improved anticancer effectiveness. High
expression of GPC1 on the pancreatic cancer cells allowed for greater cellular uptake of the
ORI-GPC1-NPs in comparison to the ORI-NPs or ORI. This research had several limitations.
While AuNCs could be employed for computed tomography imaging, researchers were unable
to undertake this experiment due to concentration restrictions. The size of the pancreatic
tumour tissue may restrict the application of NIR imaging in people.
The suggested multifunctional GPC1-targeted NPs, in general, demonstrated the selective
accumulation in pancreatic tumours by NIRF/MRI and targeted therapy in a preclinical.
Their findings imply that this multifunctional theranostic nanoplatform may provide new
opportunities for pancreatic cancer early detection and targeted therapy.
2) Isolation Of Exosomes From Whole Blood
An exosome-binding antibody (anti-CD9) was effectively functionalized with magnetic
nanoparticles (Fe3O4NPs) to mediate the magnetic capture in a microdevice. This was done in
a 1.6 mm (outside diameter) microchannel that had a set of NdFeB permanent magnets in
contact with its wall. This created a strong magnetic field across the channel's diameter,
enabling exosome separation with a high yield. Direct capture of exosomes from whole blood
of patients with pancreatic cancer (PC) was carried out to demonstrate the method's utility. The
CA19-9 protein, which is frequently used to track PC patients, was analysed from the exosomes
that had been captured. A microfluidic device was used for isolating exosomes from whole
blood without the need for any prior isolation processes, easing the process's transition to the
clinic. The findings demonstrate that, as compared to serum samples, the examination of CA19-
9 in exosomes was extremely sensitive for the cases examined. Exosome isolation and analysis
are developing as a viable approach in customised and diagnostic medicine. (Sancho-Albero et
al., 2020)The reliability of analysis is jeopardised by present procedures, which rely on rapid,
successive centrifugation stages. These methods also need for expensive equipment, highly
skilled employees, and manual operation. Instead of using a centrifugation/purification
cascade, the procedure used in the research conducted entails delivering the sample and
antibody-nanoparticle streams to a coaxial mixer, and after allowing for antibody recognition,
collecting the captured exosomes downstream. The process is substantially quicker in
comparison, and employees with only the most fundamental skills can use the gadget. The
microfluidic device was used to isolate PC-derived exosomes from whole blood as a proof of
concept, and the results demonstrate a high sensitivity of PC-marker detection in the collected
exosomes, compared to serum samples. If distinctive proteins are abundant inpatient exosomes,
the same operational concept could be applied to the diagnosis of other diseases.
3) Nucleus-Targeted Ultra-Small Metal Organic Framework
A metal-organic framework (MOF) platform based on the ultra-small, nucleus-targeted Ti-
tetrakis(4-carboxyphenyl)porphyrin (TCPP) was created and demonstrated to be a successful
Sonodynamic Therapy (SDT) mediator. In response to low-intensity ultrasonic (US) irradiation
this MOF was able to produce significant amounts of ROS in an oxygen-independent manner,
promoting type I and type II SDT.(Zhang et al., 2021) So, this method has a lot of potential for
treating solid tumours caused by extremely hypoxic orthotopic pancreatic cancer. By direct
DNA damage and triggering S phase cell cycle arrest after US irradiation, this Ti-TCPP MOF
was able to cause in vitro cellular death.
These MOF preparations' prolonged circulation, high intra tumoral accumulation, and nucleus-
targeting qualities significantly reduced the growth of orthotopic pancreatic tumours and
increased the longevity of tumor-bearing animals after Ti-TCPP+US therapy. Its activity was
in line with a potentially effective method of treating hypoxic solid tumours. Ti-TCPP MOF
was virtually completely eliminated in in vivo tests after 7 days of therapy without showing
any signs of haematological or histological damage. As a result, the nucleus-targeted Ti-TCPP
MOF platform we've developed offers a fresh, effective method for promoting SDT in response
to low-intensity ultrasound.
4) Topically Applicated Curcumin/ Gelatin-Blended Nanofbrous Mat
To significantly increase curcumin's bioavailability by local controlled release, a
curcumin/gelatin-blended nanofbrous mat was electro spun. Curcumin was found to be
uniformly dispersed in the fibre of the mats with nanoscopic dimensions and could be
continuously released into the surrounding medium for days after being characterised by
scanning electron microscopy, fluorescence microscopy, Fourier transform infrared
spectroscopy, X-ray diffraction, and high-performance liquid chromatography. By employing
pancreatic adenocarcinoma cell assays and xenograft model tests, the cancer-inhibitory effects
of nano-curcumin and underlying mechanisms were further investigated. The findings
demonstrated that, in addition to inhibiting growth of pancreatic adenocarcinoma cells in vitro,
the released nano-curcumin could also do so in vivo.(Cheng et al., 2020) This lethal effect of
nano-curcumin against pancreatic cancer was attained by inducing intracellular reactive
oxygen species and triggering endoplasmic reticulum stress, which increases cell death by
dephosphorylating signal transducer and activator of transcription. Clinically, a
curcumin/gelatin-blended nanofibrous mat may be a potential, safe, effective, and reasonably
priced substitute for cancer cells that remain following tumour removal. Furthermore, this work
used electrospinning to create curcumin-loaded gelatin nanofiber mats. Hence, the curcumin
encapsulated inside the NMs might be released gradually over several days to achieve a specific
amount in the environmental solution. Curcumin's bioavailability was significantly increased
through the controlled release, as demonstrated by in vitro and in vivo tests. Importantly, the
xenograft tumour growth in the animal model was clearly inhibited after topical application of
the curcumin/gelatin-blended nanofbrous mat. As a result, the fundamental mechanisms were
examined in more detail. In conclusion, due to its safety, efficacy, and cost-effectiveness,
electrospinning may be a potential method for the delivery of curcumin into the NMs for use
in combination therapy against pancreatic cancer and many other neoplastic illnesses.
5) Fe2P Nanorods Based Photothermal Therapy
According to Liu et al., combining PD-L1-based immunotherapy with nanorods (NRs)-
mediated photothermal therapy (PTT) is an effective treatment for pancreatic cancer. Under
low dosage 980 nm laser irradiation, the Fenton reaction, which is driven by ferrous iron,
boosted immunogenic tumour cell killing. Meanwhile, NRs were the reason for improved
antigen capture. Such exceptional qualities presented great opportunities to quicken the
activation and invasion of antigen-presenting cells and elicit a CTL response. Increased cell
death in distal tumours is evidence that the newly approved immune checkpoint inhibitor, PD-
L1, potentiated the alleviation of immunosuppression and boosted antimetastatic efficacy.
Their research offered a promising plan for the treatment of pancreatic cancer that targets both
distant metastases and primary tumour growth, opening up new opportunities for the
synergistic combination of PTT and immunotherapy in the future. (Liu et al., 2021)
6) Extracellular Matrix Modulating Enzyme Functionalized Biomimetic Au Nanoplatform
Yang et al. created a collagenase-functionalized biomimetic drug-loaded Au nanoplatform that
incorporated synergistic anticancer therapy and diagnosis with ECM degradation, active
targeting, immune evasion, and near-infrared (NIR) light-triggered drug release into one
nanoplatform. Membranes from PDAC tumour cells were isolated, coated with doxorubicin
(Dox)-loaded Au nanocages, and then functionalized via lipid insertion by collagenase.
The nanoplatform's physical and chemical characteristics, targeting, penetration, and
therapeutic efficacy were assessed. The dense ECM in the PDAC tissues was gradually broken
down by collagenase during penetration into the tumour tissue, resulting in a looser ECM
structure and deep penetration within the tumour parenchyma. The encapsulated chemotherapy
medicines were released effectively under NIR irradiation, producing both photothermal and
photodynamic effects that had a potent synergistic antitumor effect. Moreover, the X-ray
attenuation characteristics of this nanoplatform could be used to direct and monitor treatment
through CT imaging.
The researchers developed the adaptable nanoplatform Col-M@AuNCs/Dox, which combined
active targeting, immune evasion, deep penetration, PDT/PTT/chemotherapy, and CT imaging
to improve the treatment of PDAC.(Yang et al., 2022) By combining the qualities of deep
tumour penetration, enhanced tumor-killing effects, and effective imaging capability, the use
of Col-M@AuNCs/Dox provided a straightforward and effective strategy for the generation of
a multifunctional nanoplatform for the thorough elimination of PDAC. This provided an
effective solution to the treatment challenge of PDAC.
7) Dual-Targeting Biomimetic Nanomedicine
In order to create biomimetic nanomedicine that targets macrophages, (Wang et al.,
2022)suggested using exogenous transfection. The strategy makes use of the membrane
function via lentivirus transfection of an exogenous gene fragments encoding targeting groups,
in contrast to the prior methods of membrane bioengineering, such as chemical modification,
lipophilic insertion, and exogenous membrane fusion. The bioengineered membrane is
therefore endowed with the mosaic surface groups, consisting of the M2pep moiety and the
Tumor-associated antigen (TAAs), which are capable of both macrophages targeting and
cancer homing, because the KPC(a clinically relevant model of PDAC) membrane employed
in nanomedicine contains a lot of TAAs. The nanomedicine specifically targets the tumour
microenvironment, suppresses M2-like macrophages, and inhibits both cancer cell growth and
tumor-promoting activities carried out by macrophages. By enhancing the maintained
accumulation of the medicines, it also improves the therapeutic effect. Not only did this study
suggest a simple biomimetic engineering method to quicken the development of gemcitabine-
based nanomedicine, but it also defined a practical clinical method for the successful
combination of chemotherapy and immune checkpoint inhibitor therapy.
CONCLUSION
To sum it all up, PDAC can prove to be extremely lethal due to its malignancies and concurrent
as well as past researches and developments have proved to be beneficial towards decreasing
its adversity. The attempt to get rid of this problem may produce fruitful results very soon.
Be it the element nanoparticles, microfluidic devices, exosome isolation, targeting particular
cell organelles, specific treatments, bioengineered nanomedicines or the therapy for cancer
treatment, all of these have shown positive results on the model organisms and very soon, they
would show positive results in humans as well once the human trials are conducted. All the
studies discussed have shown incredible results and the advancements in technology and in the
field of science leaves us with ample opportunities to discover more and better solutions to
Pancreatic cancer and PDAC.
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