>> Modulating toxicity in photodynamic treatment (PDT, light activated) and improving imaging quality of theranostic(a) compounds to diagnose and treat cancer.

Modulating toxicity in photodynamic treatment (PDT, light activated) and improving imaging quality of theranostic(a) compounds to diagnose and treat cancer.

On October 30, 2019, Tags News, Oncology

Over the past two decades an array of targeted therapies have begun to revolutionise cancer treatment, providing better clinical outcomes in tumour types which exhibit certain biomarkers In contrast with traditional broad cytotoxic chemotherapies. Targeted therapies while more selective as inhibitors of cancer cell survival, can still have broad and severe side effect profiles for patients. These side effects can a significant impact regarding which patients can receive therapy, based on their prognosis at the start of therapy. Side effects can limit targeted therapy use to patients whose prognosis is poor enough to warrant the cons of targeted therapy or those patients who are healthy enough to tolerate the toxicity of the therapy.

Recent research into theranostics (the combination of diagnostic and therapeutic agents into an individual platform [1]) may offer a way to achieve greater selective toxicity within one group of targeted therapies (Photodynamic Therapies). A study conducted by Broadwater, D. et al [2] published this month, demonstrated an in-vitro ability to ‘modulate the cytotoxicity and phototoxicity(b) of fluorescent organic salts’ which have a high affinity for certain tumour cells.

The concept of theranostics is not new, the first iteration of its development was utilised in the 1940’s when two iodine isotopes (123I and 131I) were used for imaging and treatment of thyroid cancer [1]. 123I demonstrates an affinity to thyroid tumour cells, during its decay γ-particles are produced which are detectable using a gamma camera; 131I produces both γ- and β-particles which causes cellular damage making it an effective method of killing cancer cells [1]. Since then further radioactive theranostic drugs have been established, gradually transitioning into the development of organic and inorganic nanoparticle theranostic (see Figure 1).

 

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Figure 1. A time line of advancements in theranostic tools [1]

 

In the latest study conducted by Broadwater, D. et al, light activated nano-particulate fluorescent salts have been used in-vitro to identify (using near infrared light (NIR) emission) and kill (using induced phototoxicity(b)) human lung cancer and melanoma cells [2].

Currently fluorescent dyes within the visible light and near-infrared (NIR) range are used for imaging and photodynamic therapy (PDT, light activated therapy) for eliminating cancer cells. There are three main limiting factors in the use of fluorescent dyes:

  • the depth of penetration to affect deeply embedded tumours as light cannot travel deep enough within the body to activate the fluorophore
  • the low brightness in imaging
  • the unwanted phototoxic(b) side effects during imaging

Broadwater, D. et al has demonstrated increased brightness and depth of penetration using fluorescent salts with variations in anion pairings, which greatly improves imaging for diagnosis and observation of tumour progression; also demonstrated is an ability to independently control cytotoxic and phototoxic(b) affects based on pairing the fluorescent ion with a specific counterion, to formulate a salt which is both soluble and stable in an aqueous solution [2]. A fluorescent salt of heterocyclic polymethine cyanine (HPC) was chosen for this study as a model organic salt; HPC was selected due to its characteristic accumulation in tumours and circulating cancer cells. This is due to the over-production of organic anion transporter peptides (OATPs) and hypoxia-inducible factor 1-alpha both of which increase uptake of polymethine cyanine [2].

Control of toxicity is based on the careful selection of the anion component of the salt [2]. There are three major types of anion-(d)-cation+(c) pairings utilised to modulate toxicity:

  • A heptamethine cyanine cation(c) (Cy+, photoactive fluorescent cation(c) which emits NIR light) in combination with small hard anions- demonstrated high cytotoxicity at both high and low concentrations
  • Pairing Cy+ with a larger halogenated ion displayed nontoxic affects at high and low concentrations (ideal for imaging as large quantities can be used resulting in brighter and clearer imaging, without causing harmful side effects)
  • Pairing Cy+ with an intermediate group of anions created a fluorescent salt that is extremely phototoxic(b) but negligibly cytotoxic which fits the profile of a high-quality PDT

The independent control of both cytotoxicity and phototoxicity(b) make nano fluorescent salts with high affinity to malignant cancer cells, the ideal therapeutic tool, with a specificity that has the potential to reduce side effects associated with targeted chemotherapy. Furthermore, the increased depth of tissue penetration and the increased brightness of light provided by fluorescent salts in contrast to dyes could greatly improve imaging for disease diagnosis and progression.

The possibilities indicated by this early in-vitro study for the diagnosis and treatment of cancer are promising, further research and clinical development of theranostic tools and techniques in the future, has the potential to significantly affect oncology markets, though it is still unclear if and when this will happen. 

 

References

 [1] Kevadiya, B., D. et al. Neurotheranostics as personalized medicines. Advanced Drug delivery Reviews. 2018; https://doi.org/10.1016/j.addr.2018.10.011

[2] Broadwater, D. et al. Modulating cellular cytotoxicity and phototoxicity of fluorescent organic salts through counterion pairing. Nature. 2019;9:15288

Glossary

(a) Theranostics – a combination of both diagnosis and treatment within the same platform.

(b) Phototoxic/Phototoxicity – light induced toxic effect.

(c) Cation – a positively charged ionic constituent of a salt.

(d) Anion – the negatively charged ionic constituent of a salt.

 

Jai Bains 

Oncology Market Forecasting Analyst 

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