Radioluminescent nanoparticles for radiation-controlled release of drugs

Rahul Misra, Kaustabh Sarkar, Jaewon Lee, Vincenzo J. Pizzuti, Deborah S. Lee, Melanie P. Currie, Sandra E. Torregrosa-Allen, David E. Long, Gregory A. Durm, Mark Langer, Bennett D. Elzey, You Yeon Won

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

The present work demonstrates a novel concept for intratumoral chemo-radio combination therapy for locally advanced solid tumors. For some locally advanced tumors, chemoradiation is currently standard of care. This combination treatment can cause acute and long term toxicity that can limit its use in older patients or those with multiple medical comorbidities. Intratumoral chemotherapy has the potential to address the problem of systemic toxicity that conventional chemotherapy suffers, and may, in our view, be a better strategy for treating certain locally advanced tumors. The present study proposes how intratumoral chemoradiation can be best implemented. The enabling concept is the use of a new chemotherapeutic formulation in which chemotherapy drugs (e.g., paclitaxel (PTX))are co-encapsulated with radioluminecsnt nanoparticles (e.g., CaWO 4 (CWO)nanoparticles (NPs))within protective capsules formed by biocompatible/biodegradable polymers (e.g., poly(ethylene glycol)-poly(lactic acid)or PEG-PLA). This drug-loaded polymer-encapsulated radioluminescent nanoparticle system can be locally injected in solution form into the patient's tumor before the patient receives normal radiotherapy (e.g., 30–40 fractions of 2–3 Gy daily X-ray dose delivered over several weeks for locally advanced head and neck tumors). Under X-ray irradiation, the radioluminescent nanoparticles produce UV-A light that has a radio-sensitizing effect. These co-encapsulated radioluminescent nanoparticles also enable radiation-triggered release of chemo drugs from the polymer coating layer. The non-toxic nature (absence of dark toxicity)of this drug-loaded polymer-encapsulated radioluminescent nanoparticle (“PEG-PLA/CWO/PTX”)formulation was confirmed by the MTT assay in cancer cell cultures. A clonogenic cell survival assay confirmed that these drug-loaded polymer-encapsulated radioluminescent nanoparticles significantly enhance the cancer cell killing effect of radiation therapy. In vivo study validated the efficacy of PEG-PLA/CWO/PTX-based intratumoral chemo-radio therapy in mouse tumor xenografts (in terms of tumor response and mouse survival). Results of a small-scale NP biodistribution (BD)study demonstrate that PEG-PLA/CWO/PTX NPs remained at the tumor sites for a long period of time (> 1 month)following direct intratumoral administration. A multi-compartmental pharmacokinetic model (with rate constants estimated from in vitro experiments)predicts that this radiation-controlled drug release technology enables significant improvements in the level and duration of drug availability within the tumor (throughout the typical length of radiation treatment, i.e., > 1 month)over conventional delivery systems (e.g., PEG-PLA micelles with no co-encapsulated CaWO 4 , or an organic liquid, e.g., a 50:50 mixture of Cremophor EL and ethanol, as in Taxol), while it is capable of maintaining the systemic level of the chemo drug far below the toxic threshold limit over the entire treatment period. This technology thus has the potential to offer a new therapeutic option that has not previously been available for patients excluded from conventional chemoradiation protocols.

Original languageEnglish (US)
Pages (from-to)237-252
Number of pages16
JournalJournal of Controlled Release
Volume303
DOIs
StatePublished - Jun 10 2019

Fingerprint

Nanoparticles
Radiation
Paclitaxel
Neoplasms
Polymers
Radio
Pharmaceutical Preparations
Drug Therapy
Drug Liberation
Radiotherapy
Therapeutics
X-Rays
Colony-Forming Units Assay
Technology
Poisons
Micelles
Ultraviolet Rays
Standard of Care
Drug-Related Side Effects and Adverse Reactions
Heterografts

Keywords

  • Chemoradiation
  • Chemotherapy
  • Head and neck squamous cell carcinoma
  • Paclitaxel
  • PEG-PLA
  • Radiation-controlled drug release
  • Radioluminescent nanoparticles
  • Radiotherapy

ASJC Scopus subject areas

  • Pharmaceutical Science

Cite this

Misra, R., Sarkar, K., Lee, J., Pizzuti, V. J., Lee, D. S., Currie, M. P., ... Won, Y. Y. (2019). Radioluminescent nanoparticles for radiation-controlled release of drugs. Journal of Controlled Release, 303, 237-252. https://doi.org/10.1016/j.jconrel.2019.04.033

Radioluminescent nanoparticles for radiation-controlled release of drugs. / Misra, Rahul; Sarkar, Kaustabh; Lee, Jaewon; Pizzuti, Vincenzo J.; Lee, Deborah S.; Currie, Melanie P.; Torregrosa-Allen, Sandra E.; Long, David E.; Durm, Gregory A.; Langer, Mark; Elzey, Bennett D.; Won, You Yeon.

In: Journal of Controlled Release, Vol. 303, 10.06.2019, p. 237-252.

Research output: Contribution to journalArticle

Misra, R, Sarkar, K, Lee, J, Pizzuti, VJ, Lee, DS, Currie, MP, Torregrosa-Allen, SE, Long, DE, Durm, GA, Langer, M, Elzey, BD & Won, YY 2019, 'Radioluminescent nanoparticles for radiation-controlled release of drugs', Journal of Controlled Release, vol. 303, pp. 237-252. https://doi.org/10.1016/j.jconrel.2019.04.033
Misra, Rahul ; Sarkar, Kaustabh ; Lee, Jaewon ; Pizzuti, Vincenzo J. ; Lee, Deborah S. ; Currie, Melanie P. ; Torregrosa-Allen, Sandra E. ; Long, David E. ; Durm, Gregory A. ; Langer, Mark ; Elzey, Bennett D. ; Won, You Yeon. / Radioluminescent nanoparticles for radiation-controlled release of drugs. In: Journal of Controlled Release. 2019 ; Vol. 303. pp. 237-252.
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AU - Misra, Rahul

AU - Sarkar, Kaustabh

AU - Lee, Jaewon

AU - Pizzuti, Vincenzo J.

AU - Lee, Deborah S.

AU - Currie, Melanie P.

AU - Torregrosa-Allen, Sandra E.

AU - Long, David E.

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N2 - The present work demonstrates a novel concept for intratumoral chemo-radio combination therapy for locally advanced solid tumors. For some locally advanced tumors, chemoradiation is currently standard of care. This combination treatment can cause acute and long term toxicity that can limit its use in older patients or those with multiple medical comorbidities. Intratumoral chemotherapy has the potential to address the problem of systemic toxicity that conventional chemotherapy suffers, and may, in our view, be a better strategy for treating certain locally advanced tumors. The present study proposes how intratumoral chemoradiation can be best implemented. The enabling concept is the use of a new chemotherapeutic formulation in which chemotherapy drugs (e.g., paclitaxel (PTX))are co-encapsulated with radioluminecsnt nanoparticles (e.g., CaWO 4 (CWO)nanoparticles (NPs))within protective capsules formed by biocompatible/biodegradable polymers (e.g., poly(ethylene glycol)-poly(lactic acid)or PEG-PLA). This drug-loaded polymer-encapsulated radioluminescent nanoparticle system can be locally injected in solution form into the patient's tumor before the patient receives normal radiotherapy (e.g., 30–40 fractions of 2–3 Gy daily X-ray dose delivered over several weeks for locally advanced head and neck tumors). Under X-ray irradiation, the radioluminescent nanoparticles produce UV-A light that has a radio-sensitizing effect. These co-encapsulated radioluminescent nanoparticles also enable radiation-triggered release of chemo drugs from the polymer coating layer. The non-toxic nature (absence of dark toxicity)of this drug-loaded polymer-encapsulated radioluminescent nanoparticle (“PEG-PLA/CWO/PTX”)formulation was confirmed by the MTT assay in cancer cell cultures. A clonogenic cell survival assay confirmed that these drug-loaded polymer-encapsulated radioluminescent nanoparticles significantly enhance the cancer cell killing effect of radiation therapy. In vivo study validated the efficacy of PEG-PLA/CWO/PTX-based intratumoral chemo-radio therapy in mouse tumor xenografts (in terms of tumor response and mouse survival). Results of a small-scale NP biodistribution (BD)study demonstrate that PEG-PLA/CWO/PTX NPs remained at the tumor sites for a long period of time (> 1 month)following direct intratumoral administration. A multi-compartmental pharmacokinetic model (with rate constants estimated from in vitro experiments)predicts that this radiation-controlled drug release technology enables significant improvements in the level and duration of drug availability within the tumor (throughout the typical length of radiation treatment, i.e., > 1 month)over conventional delivery systems (e.g., PEG-PLA micelles with no co-encapsulated CaWO 4 , or an organic liquid, e.g., a 50:50 mixture of Cremophor EL and ethanol, as in Taxol), while it is capable of maintaining the systemic level of the chemo drug far below the toxic threshold limit over the entire treatment period. This technology thus has the potential to offer a new therapeutic option that has not previously been available for patients excluded from conventional chemoradiation protocols.

AB - The present work demonstrates a novel concept for intratumoral chemo-radio combination therapy for locally advanced solid tumors. For some locally advanced tumors, chemoradiation is currently standard of care. This combination treatment can cause acute and long term toxicity that can limit its use in older patients or those with multiple medical comorbidities. Intratumoral chemotherapy has the potential to address the problem of systemic toxicity that conventional chemotherapy suffers, and may, in our view, be a better strategy for treating certain locally advanced tumors. The present study proposes how intratumoral chemoradiation can be best implemented. The enabling concept is the use of a new chemotherapeutic formulation in which chemotherapy drugs (e.g., paclitaxel (PTX))are co-encapsulated with radioluminecsnt nanoparticles (e.g., CaWO 4 (CWO)nanoparticles (NPs))within protective capsules formed by biocompatible/biodegradable polymers (e.g., poly(ethylene glycol)-poly(lactic acid)or PEG-PLA). This drug-loaded polymer-encapsulated radioluminescent nanoparticle system can be locally injected in solution form into the patient's tumor before the patient receives normal radiotherapy (e.g., 30–40 fractions of 2–3 Gy daily X-ray dose delivered over several weeks for locally advanced head and neck tumors). Under X-ray irradiation, the radioluminescent nanoparticles produce UV-A light that has a radio-sensitizing effect. These co-encapsulated radioluminescent nanoparticles also enable radiation-triggered release of chemo drugs from the polymer coating layer. The non-toxic nature (absence of dark toxicity)of this drug-loaded polymer-encapsulated radioluminescent nanoparticle (“PEG-PLA/CWO/PTX”)formulation was confirmed by the MTT assay in cancer cell cultures. A clonogenic cell survival assay confirmed that these drug-loaded polymer-encapsulated radioluminescent nanoparticles significantly enhance the cancer cell killing effect of radiation therapy. In vivo study validated the efficacy of PEG-PLA/CWO/PTX-based intratumoral chemo-radio therapy in mouse tumor xenografts (in terms of tumor response and mouse survival). Results of a small-scale NP biodistribution (BD)study demonstrate that PEG-PLA/CWO/PTX NPs remained at the tumor sites for a long period of time (> 1 month)following direct intratumoral administration. A multi-compartmental pharmacokinetic model (with rate constants estimated from in vitro experiments)predicts that this radiation-controlled drug release technology enables significant improvements in the level and duration of drug availability within the tumor (throughout the typical length of radiation treatment, i.e., > 1 month)over conventional delivery systems (e.g., PEG-PLA micelles with no co-encapsulated CaWO 4 , or an organic liquid, e.g., a 50:50 mixture of Cremophor EL and ethanol, as in Taxol), while it is capable of maintaining the systemic level of the chemo drug far below the toxic threshold limit over the entire treatment period. This technology thus has the potential to offer a new therapeutic option that has not previously been available for patients excluded from conventional chemoradiation protocols.

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