5 januari 2017: lees ook dit artikel: 

https://kanker-actueel.nl/NL/pdt-photo-dynamische-therapie-op-in-bloed-circulerende-tumorcellen-lijkt-met-nieuwe-techniek-in-korte-tijd-alle-tumorcellen-te-doden-en-kan-daarmee-uitzaaiingen-en-recidieven-voorkomen.html

18 december 2021: Een recente studie over toepassing van PDT bij prostaatkanker (abstract staat onderaan artikel):  

Prostate-specific membrane antigen (PSMA)-targeted photodynamic therapy enhances the delivery of PSMA-targeted magnetic nanoparticles to PSMA-expressing prostate tumors


Hier nog een wat oudere studie over PDT bij prostaatkanker: 

Focal Therapy: A New Paradigm for the Treatment of Prostate Cancer



5 januari 2017: Bron: The Lancet 16 december 2016 online

PDT - Photo Dynamische Therapy  gericht op in bloed circulerende tumorcellen vermindert sterk de progressie van lokale prostaatkanker  bij patiënten die in een wait-and-see programma zaten in vergelijking met de patienten die geen PDT - Photo Dynamische Therapy kregen maar alleen het wait-and-see beleid volgden. Na 2 jaar bleek er in de PDT groep 58 (28%) van de 206 mannen in de PDT groep progressie van hun ziekte te vertonen tegenover 120 (58%) mannen van de 207 in de wait-and-see controlegroep (adjusted hazard ratio 0·34, 95% CI 0·24–0·46; p<0·0001)

Nog beter waren de cijfers voor een negatieve biopt 2 jaar na de PDT behandeling. 101 (49%) van de 206 mannen uit de PDT groep had een negatieve prostaat biopt vergeleken met 28 (14%) mannen van de 207 uit de wait-and-see controlegroep (adjusted risk ratio 3·67, 95% CI 2·53–5·33; p<0·0001)

Dit blijkt uit een gerandomiseerde Europese fase III studie in 47 ziekenhuizen (waaronder NKI / AvL Amsterdam en het Catharina Ziekenhuis Eindhoven) bij totaal 413 prostaatkankerpatienten. De studie is gepubliceerd in The Lancet Oncology, De studie is uitgevoerd onder leiding van de Franse Prof Abdel-Rahmène Azzouzi.

Onderstaand beeld is uit een andere studie met PDT - Photo Dynamische therapie op in bloed circulerende tumorcellen bij prostaatkankerpatienten. Tekst gaat onder dit beeld verder

PDT bij prostaatkanker

Figure 1.

Schematic diagram of treatment plans and corresponding Day-7 MRI results. The three treatment plans for focal therapy of low-risk, early stage prostate cancer by WST11-mediated VTP therapy, which were considered by the Treatment Planning Guidance Committee, are displayed. The possible different fibre configurations used are shown.The red circles indicate the possible location of the fibres; the blue circle indicates the position of the urethra in the prostate gland. The corresponding MRIs, taken on Day-7, are shown underneath.

De studie van Prof. dr. Abdel-Rahmène Azzouzi en collega's werd uitgevoerd in de periode tussen maart 2011 en april 2013 bij zoals gezegd 413 prostaatkankerpatienten die in een wait-and-see beleid zaten. (Zie studieprotocol: https://clinicaltrials.gov/show/NCT01310894)

De PDT - Fotodynamische therapie bestond uit het gebruik van de fotosensitizer padeliporfin (TOOKAD® Soluble Vascular Targeted Photodynamic therapy (VTP)) in een dosis van 4 mg / kg intraveneus gedurende 10 minuten samen met optische vezels ingebracht in de prostaat in de behandelingszone. Daarna werd de behandelingszone belicht door laserlicht van 753 nm met een gefixeerde kracht van 150 mW/cm gedurende 22 minuten en 15 seconden.

Tekst gaat onder beeld verder

Bron foto: producent van padeliporfin

PDT bij prostaatkanker met padeliporfin

Met intervallen van drie maanden werd de PSA gemeten en vond daarnaast een digitale en een handmatige controle plaats. Op 12 maanden volgde een biopt. Na 2 jaar werden de studiersultaten geanalyseerd. Met dus meer dan uitstekende resultaten op ziekteprogressie en negaiteve biopten. Wel waren er wat meer bijwekeringen bij patienten uit de PDT groep maar die waren minimaal en goed behandelbaar.

Conclusie van de onderzoekers is dan ook dat PDT - Photo Dynamische Therapy  gericht op de bloedvaten bij prostaatkankerpatienten in een wait-and-see beleid kan behoeden voor een prostaatverwijdering en verdere radicale behandeling.

Zie voor alle cijfers het abstract hieronder.

Kernpunten uit de studie:

  • Vascular-targeted photodynamic therapy was associated with a lower rate of disease progression in men with low-risk prostate cancer.
  • The treatment approach was well tolerated, and it may allow men to consider a tissue-preserving approach and defer or avoid radical therapy.

Het volledige studierapport: Padeliporfin vascular-targeted photodynamic therapy versus active surveillance in men with low-risk prostate cancer (CLIN1001 PCM301): an open-label, phase 3, randomised controlled trial is tegen betaling in te zien of te downloaden.

Deze reviewstudie van PDT - Photo Dynamische Therapy op de in bloed circulrende tumrocellen : Vascular targeted photochemotherapy using padoporfin and padeliporfin as a method of the focal treatment of localised prostate cancer - clinician’s insight is wel als volledig studierapport in te zien. 

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Hier in schema de studies die in deze review studie zijn geanalyseerd:

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Table 2

Vascular targeted photodynamic therapy using padoporfin and padeliporfin in the treatment of localised prostate cancer - clinical trials

Phase No. of patients Photosensitizer Radiation Ref.
I 10 Padoporfin, 0.1-2 mg/kg (0.1, 0.25, 1 and 2 mg/kg) 763 nm, 100-360 J/cm Weersink et al[83]
I 24 Padoporfin, 0.1-2 mg/kg 763 nm, 100, 230 and 360 J/cm Trachtenberg et al[56]
I/II 15 Padoporfin, 0.1-2 mg/kg 763 nm, 100 J/cm Gertner et al[84]
I/II 34 Padoporfin, 2 mg/kg 763 nm, 100-300 J/cm Arumainayagam et al[86]
I/II 30 Padeliporfin, 2, 4 and 6 mg/kg 753 nm, 200 and 300 J/cm https://clinicaltrials.gov/ct2/show/NCT00946881[87]
II 28 Padoporfin, 2 mg/kg 763 nm, 0.1-1000 J/cm Trachtenberg et al[57]
II 40 Padeliporfin, 2, 4 and 6 mg/kg 753 nm, 200 J/cm Arumainayagam et al[72]
II 40 Padeliporfin, 2-6 mg/kg 753 nm, 200 J/cm Quoraishi et al[74]
II 85 Padeliporfin, 4 mg/kg 753 nm, 200 J/cm Azzouzi et al[88]
II 56 Padeliporfin, 4 mg/kg 753 nm, 200 J/cm Eymerit-Morin et al[89]
II 86 Padeliporfin, 4 and 6 mg/kg 753 nm, 200 and 300 J/cm https://clinicaltrials.gov/ct2/show/-NCT00975429[90]
II 117 Padeliporfin, 4 mg/kg 753 nm, 200 J/cm Azzouzi et al[62]
II 40 Padeliporfin, 2, 4 and 6 mg/kg 753 nm, 200 J/cm Moore et al[67]
II 40 Padeliporfin, 2, 4 and 6 mg/kg 753 nm, 200 and 300 J/cm https://www.clinicaltrials.gov/ct2/show/NCT00707356[92]
II/III 86 Padeliporfin, 4 mg/kg 753 nm, 200 J/cm Azzouzi et al[91]
II/III 16 Padoporfin, 2 mg/kg 763 nm, no information on radiation fluence https://www.clinicaltrials.gov/ct2/show/-NCT00312442[93]
II/III 1 Padeliporfin, 4 mg/kg 753 nm, 200 J/cm Azzouzi et al[94]
II/III 19 Padeliporfin, 4 and 6 mg/kg 753 nm, 200 and 300 J/cm Lebdai et al[95]
III 81 Padeliporfin, 4 mg/kg 753 nm, 200 J/cm https://clinicaltrials.gov/ct2/show/-NCT01875393[96]
III 400 Padeliporfin, 4 mg/kg 753 nm, 200 J/cm https://clinicaltrials.gov/show/-NCT01310894[97]

Hier de abstracten van de studies met een referentielijst.

Padeliporfin vascular-targeted photodynamic therapy is a safe, effective treatment for low-risk, localised prostate cancer. This treatment might allow more men to consider a tissue-preserving approach and defer or avoid radical therapy.

Padeliporfin vascular-targeted photodynamic therapy versus active surveillance in men with low-risk prostate cancer (CLIN1001 PCM301): an open-label, phase 3, randomised controlled trial

Prof Abdel-Rahmène Azzouzi, MD
,
Prof Sébastien Vincendeau, MD
,
Prof Eric Barret, MD
,
Prof Antony Cicco, MD
,
François Kleinclauss, MD
,
Henk G van der Poel, MD
,
Prof Christian G Stief, MD
,
Prof Jens Rassweiler, MD
,
Georg Salomon, MD
,
Prof Eduardo Solsona, MD
,
Prof Antonio Alcaraz, MD
,
Prof Teuvo T Tammela, MD
,
Derek J Rosario, MD
,
Francisco Gomez-Veiga, MD
,
Göran Ahlgren, MD
,
Fawzi Benzaghou, MD
,
Bertrand Gaillac, MD
,
Billy Amzal, PhD
,
Frans M J Debruyne, MD
,
Gaëlle Fromont, MD
,
Prof Christian Gratzke, MD
,
Prof Mark Emberton, FMedScicorrespondencePress enter key for correspondence information
on behalf of the PCM301 Study Group
Published: 19 December 2016
Article has an altmetric score of 1346

DOI: http://dx.doi.org/10.1016/S1470-2045(16)30661-1

Summary

Background

Vascular-targeted photodynamic therapy, a novel tissue-preserving treatment for low-risk prostate cancer, has shown favourable safety and efficacy results in single-arm phase 1 and 2 studies. We compared this treatment with the standard of care, active surveillance, in men with low-risk prostate cancer in a phase 3 trial.

Methods

This randomised controlled trial was done in 47 European university centres and community hospitals. Men with low-risk, localised prostate cancer (Gleason pattern 3) who had received no previous treatment were randomly assigned (1:1) to vascular-targeted photodynamic therapy (4 mg/kg padeliporfin intravenously over 10 min and optical fibres inserted into the prostate to cover the desired treatment zone and subsequent activation by laser light 753 nm with a fixed power of 150 mW/cm for 22 min 15 s) or active surveillance. Randomisation was done by a web-based allocation system stratified by centre with balanced blocks of two or four patients. Best practice for active surveillance at the time of study design was followed (ie, biopsy at 12-month intervals and prostate-specific antigen measurement and digital rectal examination at 3-month intervals). The co-primary endpoints were treatment failure (histological progression of cancer from low to moderate or high risk or death during 24 months' follow-up) and absence of definite cancer (absence of any histology result definitely positive for cancer at month 24). Analysis was by intention to treat. Treatment was open-label, but investigators assessing primary efficacy outcomes were masked to treatment allocation. This trial is registered with ClinicalTrials.gov, number NCT01310894.

Findings

Between March 8, 2011, and April 30, 2013, we randomly assigned 206 patients to vascular-targeted photodynamic therapy and 207 patients to active surveillance. Median follow-up was 24 months (IQR 24–25). The proportion of participants who had disease progression at month 24 was 58 (28%) of 206 in the vascular-targeted photodynamic therapy group compared with 120 (58%) of 207 in the active surveillance group (adjusted hazard ratio 0·34, 95% CI 0·24–0·46; p<0·0001). 101 (49%) men in the vascular-targeted photodynamic therapy group had a negative prostate biopsy result at 24 months post treatment compared with 28 (14%) men in the active surveillance group (adjusted risk ratio 3·67, 95% CI 2·53–5·33; p<0·0001). Vascular-targeted photodynamic therapy was well tolerated. The most common grade 3–4 adverse events were prostatitis (three [2%] in the vascular-targeted photodynamic therapy group vs one [<1%] in the active surveillance group), acute urinary retention (three [2%] vs one [<1%]) and erectile dysfunction (two [1%] vs three [1%]). The most common serious adverse event in the vascular-targeted photodynamic therapy group was retention of urine (15 patients; severe in three); this event resolved within 2 months in all patients. The most common serious adverse event in the active surveillance group was myocardial infarction (three patients).

Interpretation

Padeliporfin vascular-targeted photodynamic therapy is a safe, effective treatment for low-risk, localised prostate cancer. This treatment might allow more men to consider a tissue-preserving approach and defer or avoid radical therapy.

Funding

Steba Biotech.

References

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These results suggest that PSMA-targeted PDT enhances the delivery of PSMA-targeted MNPs to PSMA(+) tumors by enhancing the vascular permeability of the tumors.

 2021; 5(2): 182–196.
Published online 2021 Jan 19. doi: 10.7150/ntno.52361
PMCID: PMC7868004
PMID: 33564617

Prostate-specific membrane antigen (PSMA)-targeted photodynamic therapy enhances the delivery of PSMA-targeted magnetic nanoparticles to PSMA-expressing prostate tumors

Ethel J. Ngen,1 Ying Chen,1 Babak Behnam Azad,1 Srikanth Boinapally,1 Desmond Jacob,1 Ala Lisok,1 Chentian Shen,1 Mir S. Hossain,1 Jiefu Jin,1 Zaver M. Bhujwalla,1,2 Martin G. Pomper,1,2 and Sangeeta R. Banerjee1,2,3,✉
Author information Article notes Copyright and License information Disclaimer

Associated Data

Supplementary Materials

Abstract

Enhanced vascular permeability in tumors plays an essential role in nanoparticle delivery. Prostate-specific membrane antigen (PSMA) is overexpressed on the epithelium of aggressive prostate cancers (PCs). Here, we evaluated the feasibility of increasing the delivery of PSMA-targeted magnetic nanoparticles (MNPs) to tumors by enhancing vascular permeability in PSMA(+) PC tumors with PSMA-targeted photodynamic therapy (PDT).

Method: PSMA(+) PC3 PIP tumor-bearing mice were given a low-molecular-weight PSMA-targeted photosensitizer and treated with fluorescence image-guided PDT, 4 h after. The mice were then given a PSMA-targeted MNP immediately after PDT and monitored with fluorescence imaging and T2-weighted magnetic resonance imaging (T2-W MRI) 18 h, 42 h, and 66 h after MNP administration. Untreated PSMA(+) PC3 PIP tumor-bearing mice were used as negative controls.

Results: An 8-fold increase in the delivery of the PSMA-targeted MNPs was detected using T2-W MRI in the pretreated tumors 42 h after PDT, compared to untreated tumors. Additionally, T2-W MRIs revealed enhanced peripheral intra-tumoral delivery of the PSMA-targeted MNPs. That finding is in keeping with two-photon microscopy, which revealed higher vascular densities at the tumor periphery.

Conclusion: These results suggest that PSMA-targeted PDT enhances the delivery of PSMA-targeted MNPs to PSMA(+) tumors by enhancing the vascular permeability of the tumors.

Discussion

MNP-induced hyperthermia is currently being evaluated as a less morbid focal therapy for intermediate and high-risk localized prostate cancers , , . However, since the delivery of high concentrations of MNPs to tumors after intravenous administration is still a major challenge, current preclinical and clinical practices involve directly injecting the MNPs into tumors , . Direct injection can produce treatment-related morbidity, which can negatively impact the quality of life of patients post-treatment, and will miss metastatic foci .

Previously, we evaluated the feasibility of specifically enhancing the delivery of a PSMA-targeted MNP to PSMA(+) tumors in a preclinical dual PSMA(+) and PSMA(-) human prostate tumor mouse model, with high tumor vascular permeability . Tumor vascular permeability was modulated in that study by using large tumors (~250 mm3). In that study, we observed that although administering high MNP doses [50 mg/kg (30 mg of Fe/kg)] increased the amount of MNPs that accumulated in PSMA(+) tumors, it also increased the concentration of the MNPs that accumulated non-specifically in PSMA(-) tumors and the organs of the reticuloendothelial system (RES).

In this report, we evaluated a different strategy to enhance specifically the delivery of PSMA-targeted MNPs to PC tumors. We used our previously developed low-molecular-weight PSMA-targeted photosensitizer (YC-9) and a PDT pretreatment plan to enhance the vascular permeability of PSMA(+) tumors, with low tumor vascular permeability (~50 mm3), for the increased delivery of our previously developed PSMA-targeted MNPs [50 mg/kg (30 mg of Fe/kg)].

To estimate the contribution from the baseline tumor vascular permeability on MNP delivery in the PSMA(+) and PSMA(-) tumors, respectively, we estimated MNP delivery to the untreated PSMA(+) tumors (Group 3) and the untreated PSMA(-) tumors (Group 5), respectively. Using ex vivo fluorescence imaging (Table S3 and S5), we observed that the delivery of MNPs to the untreated PSMA(-) tumors (Group 5) was ~ 4.5-fold higher than to the untreated PSMA(+) tumors (Group 3). This suggested a higher contribution from the baseline vascular permeability in the PSMA(-) tumors compared to the PSMA(+) tumors. This difference was attributed to larger volumes of the PSMA(-) tumors than the PSMA(+) tumors. Thus, to take into account this baseline difference in the vascular permeability between the PSMA(+) and the PSMA(-) tumors in this study, direct comparisons were not made between the PDT pretreated PSMA(+), and the PDT pretreated PSMA(-) tumors. Instead, an indirect comparison was made as described below.

To evaluate the non-specific contributions from non-targeted PDT to enhance MNP delivery, tumors from PDT pretreated PSMA(-) PC3 flu (Group 4) mice were compared to those from untreated PSMA(-) PC3 flu (Group 5) mice. In vivo fluorescence and MRI results suggested a 3.6 ± 1.6-fold higher delivery of the MNPs in the PDT pretreated PSMA(-) tumors (Group 4), compared to the untreated PSMA(-) tumors (Group 5).

The contribution from PSMA-targeted PDT to enhance MNP delivery to tumors was next indirectly evaluated by comparing the difference between the PSMA(+) PC3 PIP groups versus that between the PSMA(-) PC3 flu groups [(Group 2 versus Group 3) compared to (Group 4 versus Group 5)]. From the in vivo fluorescence and MRI results, a 8.9 ± 2.6-fold higher delivery of the MNPs was detected in the PDT pretreated PSMA(+) tumors (Group 2), compared to the untreated PSMA(+) tumors (Group 3). Thus, by comparing the difference between the PSMA(+) groups to the difference between the PSMA(-) groups, the ~ 2-fold higher difference detected between the PSMA(+) groups was attributed to the specific contribution from PSMA-targeted PDT. These EPR effect enhancement values are comparable to those observed with other previously reported agents, designed for different tumor phenotypes , , .

Using the ex vivo fluorescence organ biodistribution ratios, we estimated that ~0.34 mg of iron/cm3 of the tumor volume was deposited in the PDT pretreated PSMA(+) tumors versus ~0.07 mg of iron/cm3 of the tumor volume in the non-treated PSMA(+) tumors. That iron concentration determined in the PDT-pretreated PSMA(+) tumors is higher than that reported to be required for efficient hyperthermia therapy (0.27 mg of iron/cm3 of the tumor volume), following direct tumor injections in rodents . However, the intra-tumoral MNP distribution was inhomogeneous. This could leave some tumor areas untreated and subsequently result in tumor regrowth and patient relapse , . Consequently, several strategies are currently being developed to homogenously enhance tumor vascular permeability and the delivery of MNPs to tumors , , . Furthermore, although this PDT pretreatment strategy was effective in enhancing the delivery of PSMA-targeted MNPs to PSMA(+) tumors with low tumor vascular permeability, there is still a need for the development and optimization of MNP delivery strategies to increase the delivery efficiency, by minimizing the accumulation of MNPs in organs of the RES, such as the liver.

Conclusion

We evaluated the feasibility of increasing the delivery of PSMA-targeted MNPs to PSMA(+) tumors with low tumor vascular permeability. Through the use of two complementary imaging techniques, we demonstrated that the delivery of PSMA-targeted MNPs to PSMA(+) tumors could be enhanced by PSMA-targeted PDT using a low-molecular-weight PSMA-targeted photosensitizer via the enhancement of tumor vascular permeability. MNP-induced hyperthermia and vascular-targeted PDT are both focal therapies currently being evaluated for the treatment of localized PC. Consequently, the use of low dose PSMA-targeted PDT to enhance the delivery of PSMA-targeted MNPs could contribute synergistically to effective long-term control of aggressive localized PC lesions. We anticipate that this strategy could be used to deliver drug-loaded, PSMA-targeted MNPs to localized, aggressive, PSMA-expressing, castration-resistant prostate tumors for enhanced MRI/MPI-guided hyperthermia, and sustained drug release.

Acknowledgments

We would like to thank Dr. Jiadi Xu and Ms. Kazi Akhter for their assistance with the MRI acquisitions. This research was sponsored by the National Institutes of Health (grant numbers: R01CA134675, U01CA183031, P50CA058236, P41EB024495, and R21HD097357).

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Articles from Nanotheranostics are provided here courtesy of Ivyspring International Publisher

PDT, Photo Dynamische Therapie, PDT op in bloed circulerende tumorcellen, prostaatkanker, wait-and-see, padeliporfin, fotosensitizers, ziekteprogressie, overall overleving, PSA


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