The objective of this application is to (I) design and synthesize photoresponsive fullerenyl enantiomers and related nanostructures as photosensitizers for PDT applications and (ii) carry out in vitro and in vivo biostudies of amphiphilic multifunctional fullerenyl enantiomers and chromophore nanostructures as 1PA-PDT and 2PA-PDT (2-3 absorptive) nanomedicines. We propose to design and synthesize novel cationic stereoregular 1-pyrrolinofullerenyl enantiomers PF-PhOEGn and cationic C60(>CPAF-EG6)x for the use as PDT agents with the following characteristics: (1) high photo stability for multiple PDT treatments with only a single-dose of the drug;(2) enhancement of light-harvesting capability using the C60-antenna construction, for cytotoxic ROS production;(3) capability of molecular self-assembly of C60-antenna forming stable vesicles for high volume delivery of PDT drug;(4) large enhancement of two-photon absorption cross-sections [>4500 GM for C60- (antenna)2] for effective 2PA-PDT treatments. We have established some of the molecular structural features of fullerenes that mediate broad-spectrum photokilling of microbial cells and cancer cells. This insight into required structural motifs has been applied to the molecular design of fullerene nanomedicines. We will study PDT efficiency by both in vitro and in vivo experiments: (1) we have assembled a panel of pathogenic microorganisms designed to encompass most of the microbes that cause localized infections e.g. in wounds and burns, and which demonstrate both intrinsic and acquired multi-antibiotic resistance. Polycationic fullerenes will be tested as PDT agents against these pathogens. (2) For fullerene-mediated PDT treatment against localized infections we will study a mouse model of wound infection using genetically engineered bioluminescent bacteria combined with optical imaging to follow the progress of the infection non-invasively in real time. (3) We will carry out in vitro PDT against a panel of mouse cancer cell lines that are expected to have different uptakes of fullerenes and different cellular responses to reactive oxygen species produced by PDT. Dose response studies of both drug and light will be carried out for both 1-photon and 2-photon excitation and mechanisms of cell death studied. (4) For anti-cancer testing we will use subcutaneous mouse tumors and compare intratumoral injection with IV delivery of the fullerene. We will compare both 1-photon excitation using a KTP laser and 2-photon excitation using a femtosecond Ti:sapph laser.
The fullerene nanomedicines described in this application have the potential to mediate photodynamic therapy of two of the major killer diseases of the present age. Multi-drug resistant bacterial infections and cancerous tumors could be eliminated by a combination of the appropriate molecular design of fullerene and illumination with CW or femtosecond pulsed light. Particular chemical and photophysical features of these compounds proposed herein will improve PDT of these diseases beyond what is presently possible.
|Yu, Chi; Avci, Pinar; Canteenwala, Taizoon et al. (2016) Photodynamic Therapy with Hexa(sulfo-n-butyl)Fullerene Against Sarcoma In Vitro and In Vivo. J Nanosci Nanotechnol 16:171-81|
|Zhang, Yunsong; Dai, Tianhong; Wang, Min et al. (2015) Potentiation of antimicrobial photodynamic inactivation mediated by a cationic fullerene by added iodide: in vitro and in vivo studies. Nanomedicine (Lond) 10:603-14|
|Yin, Rui; Wang, Min; Huang, Ying-Ying et al. (2015) Antimicrobial photodynamic inactivation with decacationic functionalized fullerenes: oxygen-independent photokilling in presence of azide and new mechanistic insights. Free Radic Biol Med 79:14-27|
|Huang, Ying-Ying; Sharma, Sulbha K; Yin, Rui et al. (2014) Functionalized fullerenes in photodynamic therapy. J Biomed Nanotechnol 10:1918-36|
|Huang, Liyi; Wang, Min; Dai, Tianhong et al. (2014) Antimicrobial photodynamic therapy with decacationic monoadducts and bisadducts of fullerene: in vitro and in vivo studies. Nanomedicine (Lond) 9:253-66|
|Yin, Rui; Wang, Min; Huang, Ying-Ying et al. (2014) Photodynamic therapy with decacationic fullerene monoadducts: effect of a light absorbing electron-donor antenna and micellar formulation. Nanomedicine 10:795-808|
|Prates, Renato A; Fuchs, Beth Burgwyn; Mizuno, Kazue et al. (2013) Effect of virulence factors on the photodynamic inactivation of Cryptococcus neoformans. PLoS One 8:e54387|
|Gupta, Asheesh; Avci, Pinar; Sadasivam, Magesh et al. (2013) Shining light on nanotechnology to help repair and regeneration. Biotechnol Adv 31:607-31|
|Huang, L; Wang, M; Sharma, S K et al. (2013) Decacationic Fullerene Approach for Efficient Photokilling of Infectious Bacteria and Cancer Cells. ECS Trans 45:|
|Jeon, Seaho; Haley, Joy; Flikkema, Jonathan et al. (2013) Linear and Nonlinear Optical Properties of Photoresponsive Fullerene Hybrid Triads and Tetrads with Dual NIR Two-Photon Absorption Characteristics. J Phys Chem C Nanomater Interfaces 117:17186-17195|
Showing the most recent 10 out of 27 publications