Nanoradioliposomes molecularly modulated to study the lung deep lymphatic drainage

Maria Filomena Rabaça Roque Botelho 1

Maria Alcide Tavares Marques 2

Célia Maria Freitas Gomes 1

Augusto Marques Ferreira da Silva 3

Vasco António Andrade Figueiredo Bairos 4

Manuel Amaro de Matos Santos Rosa 5

João José Pedroso de Lima 1

Abstract

Lung deep lymphatic drainage (LDLD) plays an important role in the removal of foreign materials from lungs being alveolar macrophages the first line of phagocytic defence with high affinity for pathogenic microorganisms. Bacillus subtilis is a well-known genome-decoded saprophyte of the human respiratory tract used in research and in the biotechnology industry.

Lung deep lymphatic chains (LDLC) constitute one of the first sites of lung tumours’ dissemination. In this work we intended to develop and validate a non-invasive method for assessing LDLC by nanoradioliposomes aerosolised modulated on the Bacillus subtilis spore wall. The final goal was to produce a nanoradioliposome formulation that can mimics the dynamics of preferential removal of spores by LDLD and present the ideal properties as a tracer for molecular imaging studies.

Seven different liposomal formulations were tested, and the formulation-F demonstrated physicochemical and radiopharmaceutical properties that make it an ideal candidate as an in vivo probe for molecular imaging studies of the LDLC.

Nanoradioliposomes of the formulation-F after labelling with 99mTc-HMPAO were administered as aerosols to 20 Sus scrofa. Hilar and interpulmonary communications were visualized in first 5 minutes post-inhalation, infradiaphragmatic chains between 10 and 20 minutes, the ganglia of the aortic chain at 20 minutes and those of the renal hilar region at 30 minutes.

Conclusion: the proposed method enables visualization of deep lymphatic lung network and lymph nodes. Besides, this technique involving the modulation of nanoradioliposomes targeting specific organs or tissues may be an important tool for diagnostic or even for therapeutic purposes.

Nanorradiolipossomas modulados molecularmente para estudar a drenagem linfática pulmonar profunda

 Resumo

A drenagem linfática pulmonar profunda (DLPP) desempenha um papel importante na remoção de materiais estranhos, constituindo os macrófagos alveolares a primeira linha de defesa fagocitária, dada a grande afinidade para microrganismos patogénicos.

Os Bacillus subtilis são saprófitas do tracto respiratório humano com ampla utilização em investigação e em biotecnologia.

As cadeias linfáticas pulmonares profundas (CLPP) constituem um dos primeiros locais de disseminação de tumores pulmonares.

Neste trabalho pretendeu-se desenvolver e validar um método não invasivo para avaliar as CLPP através de nanorradiolipossomas aerosolisados e modulados pela parede do esporo do Bacillus subtilis. O objectivo final foi produzir uma formulação de nanorradiolipossomas capaz de imitar a dinâmica da remoção de esporos pelas CLPP e simultaneamente ter propriedades ideais como traçador para imagiologia molecular.

Testámos sete diferentes formulações lipossómicas, tendo a formulação F demonstrado possuir propriedades fisicoquímicas e radiofarmacêuticas que a tornam o traçador ideal para imagiologia molecular in vivo das CLPP.

Em conclusão, o método proposto visualiza os gânglios linfáticos e a rede linfática pulmonar profunda. A modulação dos nanorradiolipossomas permite que eles atinjam órgãos ou tecidos específicos, conferindo-lhes importantes potencialidades no âmbito do diagnóstico e/ou da terapêutica.

Palavras-chave: Nanorradiolipossomas, modulação molecular, drenagem linfática pulmonar, imagem nuclear funcional

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1 Instituto de Biofísica e Biomatemática, Faculdade de Medicina, Universidade de Coimbra, Azinhaga de Santa Comba, Celas, 3000-548 Coimbra, Portugal

2 Departmento de Ciências Pneumológicas e Alergológicas, Hospitais da Universidade de Coimbra, Praceta Mota Pinto, 3000-075 Coimbra, Portugal

3 Departmento de Electrónica e Telecomunicações, Universidade de Aveiro, 3810-193 Aveiro, Portugal

4 Instituto de Histologia e Embriologia, Faculdade de Medicina, Universidade de Coimbra, Rua Larga, 3004-504 Coimbra, Portugal

Correspondência/Correspondence to:

Maria Filomena Botelho

Instituto de Biofísica e Biomatemática

IBILI-Faculdade de Medicina

Azinhaga de Santa Comba, Celas

3000-548 Coimbra

Portugal

FAX: +351 239 480258

Email: filomena@ibili.uc.pt

Recebido para publicação/received for publication: 09.01.23

Aceite para publicação/accepted for publication: 09.01.26