Image-guided photo-therapeutic nanoporphyrin synergized HSP90 inhibitor in patient-derived xenograft bladder cancer model

Abstract

Photodynamic therapy is a promising and effective non-invasive therapeutic approach for the treatment of bladder cancers. Therapies targeting HSP90 have the advantage of tumor cell selectivity and have shown great preclinical efficacy. In this study, we evaluated a novel multifunctional nanoporphyrin platform loaded with an HSP90 inhibitor 17AAG (NP-AAG) for use as a multi-modality therapy against bladder cancer. NP-AAG was efficiently accumulated and retained at bladder cancer patient-derived xenograft (PDX) over 7 days. PDX tumors could be synergistically eradicated with a single intravenous injection of NP-AAG followed by multiple light treatments within 7 days. NP-AAG mediated treatment could not only specifically deliver 17AAG and produce heat and reactive oxygen species, but also more effectively inhibit essential bladder cancer essential signaling molecules like Akt, Src, and Erk, as well as HIF-1α induced by photo-therapy. This multifunctional nanoplatform has high clinical relevance and could dramatically improve management for bladder cancers with minimal toxicity.

Nanoparticle-Based Drug Delivery in Cancer Therapy and Its Role in Overcoming Drug Resistance

“…Mitochondria-targeted NPs (Wang et al, 2020) Hypoxia Silence the HIF-1α gene HIF-1α siRNA (Zhao et al, 2015;Luan et al, 2018;Hajizadeh et al, 2020) Inhibit the function of HIF-1α HIF-1α inhibitors (Reddy et al, 2011) Indirectly downregulate HIF-1α expression Inhibitors of the PI3K/Akt/mtor pathway (Zhang et al, 2018) HSP90 inhibitors (Long et al, 2018) Abbreviations: Bcl-2 = B cell lymphoma-2; COX-2 = cyclooxygenase 2; HIF-1α = hypoxia-inducible factor 1α; HSP90 = heat shock protein 90; NF-κB = nuclear factor kappa B; NPs = nanoparticles; P-gp = P-glycoprotein; PI3K = phosphoinositol-3-kinase; siRNA = small interfering RNA.…”

One-bead one-compound combinatorial library derived targeting ligands for detection and treatment of oral squamous cancer

“…Meanwhile, we are exploiting the use of LLY13 as a selective targeting agent for delivery of imaging probe and nanotherapeutic agent against OSC, similar to other targeting ligands developed in the Lam laboratory [28, 32, 33]. We expect that LLY13 will further enhance the therapeutic efficacy of the recently reported photo-responsive micellar nanoparticles against OSC xenografts in athymic mice [34, 35]. Finally, as LLY13 is cyclic and contains some D-amino acids and unnatural amino acids, it is expected to resist proteolytic degradation and be stable for in vivo application.…”

Avaliação De Proteínas De Choque Térmico Em Células Neoplásicas De Laringe (Hep-2) Após Tratamento Fotodinâmico

“…Neste estudo, a possível presença de HSP90 no gel de eletroforese no grupo TFD 72 horas foi entendido como uma reação citoprotetora contra o estresse causado pela TFD, ou a busca por sobrevivência em ambiente hostil, já que o meio de cultura não foi renovado e a sua metabolização excessiva pode ter colocado estas células sob estresse. Nesses casos, para reduzir a possibilidade de recidiva tumoral após estresse, alguns estudos demonstram que a utilização de inibidores específicos de HSP são capazes de gerar efeito antitumoral esperado, tanto in vitro como in vivo, promovendo o desarranjo da HSP, impedindo sua ligação a outras moléculas, gerando o acúmulo de citocromo C no citoplasma, ativação das caspases para via apoptótica, formação de EROs, reduzindo a proliferação e a viabilidade celular, inibe a resistência mediada por HSPs, induz resposta imune específica para o antígeno, inibindo a angiogênese e a progressão tumoral (GUERRERO-ROJAS; GUERRERO-FONSECAZ, HUANG et al, 2018;LONG et al, 2018;KANEKO et al, 2017;LORENZO;VINTRÓ;MADRID, 2016).…”