Ingegnerizzazione della superficie di nanoparticelle upconverting per il trattamento combinato del cancro.

Responsabili di progetto

Marta Maria Natile, Daniel Horak

Accordo

REPUBBLICA CECA - CAS (ex AVCR) - Czech Academy of Sciences

Bando

CNR/CAS triennio 2019-2021 2019-2021

Dipartimento

Scienze chimiche e tecnologie dei materiali

Area tematica

Scienze chimiche e tecnologie dei materiali

Stato del progetto

Nuovo

Proposta di ricerca

Nowadays, combined cancer therapy is becoming more popular in clinics because it generates synergistic anti-cancer effects, reduces individual drug-related toxicity and suppresses multi-drug resistance.[1] All this allows improving the cure and survival rates of cancer patients. In this context, nanoparticles-based drug delivery systems exhibit a great potential due to their easy manipulation, great versatility and ability to cross biological barriers.[2]
This proposal aims to develop all-in-one systems based on multifunctional lanthanoid-doped upconverting nanoparticles (UCNPs) which can "smartly" integrate several therapeutic modalities into a single system. Two modes can complement or cooperate with each other in a synergistic way, yielding superadditive therapeutic effects. Moreover, integration of imaging with therapeutics (imaging-guided drug delivery) can simultaneously improve diagnostic precision, predict therapeutic responses, and evaluate the drug efficacy longitudinally.
UCNPs have the unique ability to emit UV-visible light under NIR excitation through a non-linear anti-Stokes process. Other advantages are their high thermal and chemical stability, negligible autofluorescence background, minimal photodamage, and low in vivo toxicity even in the conditions of long circulation. Photodynamic therapy (PDT) is an effective non-invasive clinical approach for early-stage inoperative tumors and adjuvant treatment for late-stage cancer after surgery.[3] The use of UCNPs as carrier and photo-transducer to activate the photosensitizer (PS) (by FRET) provides a robust strategy to overcome the main drawback in current PDT (low tissue penetration UV-vis light is used), since the NIR-light falling in the "therapeutic window" enables maximal light penetration (up to few centimeters) into biological tissue.[3] However, relying on the oxygen presence, PDT is not suitable for the treatment of hypoxic tumors. Several advantages will derive by combining PDT with radiotherapy (RT) and photothermal therapy (PTT). Thermal effects increasing intratumoral blood flow favor the transport of more oxygen into the tumor;[4] while cancer cells treated by X-ray irradiation seem to be more sensitive to singlet oxygen, inhibiting the DNA repair and permanently causing the cell death.[4]
The application of UCNPs for combined therapy is still in its early stage because of i) complexity in fabricating functional UCNPs composites, ii) difficulty in design of rational combination therapy, and iii) their poor own UC efficiency which requires relatively high-power density. Moreover, 980 nm excitable UCNPs are used. Several approaches including host lattice manipulation, size optimization, and in particular, surface engineering have to be considered to address all these challenges and fulfill the translation from the bench to the bedside.
The proposal is organized in three interconnected activities.
1. Synthesis of monodispersed core-shell UCNP excitable at 800 nm (e.g NaY(Gd)F4:Yb3+/Er3+(Tm3+)@NaYF4:Yb3+,Nd3+@NaYF4). Doping with paramagnetic Gd3+ will allow simultaneous magnetic resonance (MR) and UC luminescence (UCL) imaging[5] and make them qualified as radiosensitizers to enhance RT; Nd3+ doping will shift the excitation from 980 to 800 nm preventing overheating. The outermost inert layer will improve the UCL minimizing the quenching effect. A careful tuning of the working conditions will allow a fine control of the UCNPs size.(CNR)
2. Surface engineering of UCNPs for all-in-one system.
2.1 Coating with biocompatible polymers, e.g. poly(N,N-dimethylacrylamide), or new bisphosphonate-based polymers will ensure long-term colloidal stability of UCNPs in physiological media and endow UCNPs with reactive groups to facilitate subsequent covalent coupling with biomolecules, therapeutic agents, PS.(CAS,CNR)
2.3 Addressing peptides, such as azidopentanoyl-derivative of RGD or azidopentanoyl-derivative of TAT peptide will be integrated to improve NPs adhesion to the cells or to facilitate NPs cell internalization.(CAS)
2.4 Immobilization of chelators for 64Cu (99mTc) or phenolic agents for direct radiodination (125I) will enable integration of UCL with the PET or SPECT/CT imaging.[6](CAS)
2.5 To enhance UC efficiency and at the same time photothermal effect, the UCNPs surface will be decorated with Au/Ag plasmonic NPs produced by Pulsed Laser Ablation in Liquid (PLAL), which allows a fine tuning of plasmonic properties by controlling shape, agglomeration and dimension of NPs.(CNR)
3. Biological test and multifunctional evaluation.
3.1 Adhesion to cell surface, phagocytosis, cell localization and toxicity will be assessed by confocal microscopy. Various imaging (optical, MR, PET, SPECT/CT) and therapeutic modalities (PDT, RT, PTT) will be evaluated and particles pharmacokinetics will be determined.(CAS)
3.2 Combined therapeutic effects will be evaluated by preclinical NIR-PDT/RT and NIR-PDT/PTT tests on mice with xenotransplanted human tumors.(CAS)
The prepared systems will be carefully characterized at each step from structural, morphological chemical, photophysical and biological point of view with state-of-the art facilities available at the two institutions.
The scientific expertise of the two teams involved in this proposal is perfectly complementary, as detailed below.
The CNR team has deep expertise mainly in synthesis and characterization of colloidal UCNPs and plasmonic NPs obtained by PLAL strategy.
The CAS team has deep expertise in synthesis of new molecules, polymers, addressing peptides for surface engineering of UCNPs. The CAS team can take advantage of the consolidate collaboration with the Center of Advanced Preclinical Imaging in Prague for experiments on cells and animal tumors and PET, SPECT, CT and MRI imaging.
[1]Nat. Biotechnol. 2009,27,659
[2]Chem. Rev. 2017,117,13566
[3]Adv. Mater. 2015,27,7692
[4]Sci. Rep. 2016,6,34796
[5]Int. J. Nanomed. 2017,12,1
[6]Chem. Soc. Rev. 2015,44,1302

Obiettivi della ricerca

This collaborative project aims at design of a biocompatible nanoplatform based on 800-UCNPs that provide multimodal synergetic therapy (NIR-PDT/RT or NIR-PDT/PTT) and imaging.
At an increasing level of complexity, the project aims to reach the following goals.
1.Obtaining a nanoplatform, which strongly absorbs at 800nm allowing deep penetration through biological tissues with minimal damage deriving from overheating.
2.Increasing the quantum yield of UCNPs by surface passivation through a properly optimized core-shell structure and/or surface plasmon coupling in order to use a relatively low and human-safe power density (few mWcm-2) for UCNPs excitation.
3.Addressing surface functionalization to get long-term stable dispersion of UCNPs, prolong the blood circulation time, enhance their active targeting efficiency and add therapeutic/diagnostic functionalities.
4.Realizing a rational combination of two therapeutic modalities on the same nanoplatform for a better therapeutic efficacy.
5.Integrating imaging functionalities for a simultaneous deep-body diagnostic.
6.Increasing the interaction between our research groups and our Institutions; this project will be a basis for future joint applications in European calls.
Our results (through dissemination by papers, seminars, participation at conferences, etc.) will contribute to shedding fundamental insight in development of combined cancer therapy and, then, will have a considerable impact on the scientific community.

Ultimo aggiornamento: 03/05/2024