Near-Infrared Activatable Phthalocyanine–Poly-L-Glutamic Acid Conjugate: Enhanced in Vivo Safety and Antitumor Efficacy toward an Effective Photodynamic Cancer Therapy

Abstract

We previously developed a new zinc(II) phthalocyanine (ZnPc) derivative (Pc 1) conjugated to poly-L-glutamic acid (PGA) (1-PG) to address the limitations of ZnPc as part of an antitumor photodynamic therapy approach, which include hydrophobicity, phototoxicity, and nonselectivity in biodistribution and tumor targeting. During this study, we discovered that 1-PG possessed high near-infrared (NIR) light absorptivity (λ = 675 nm), good singlet oxygen generation efficiency in an aqueous environment, and enhanced photocytotoxic efficacy and cancer cell uptake in vitro. In the current study, we discovered that 1-PG accumulated in 4T1 mouse mammary tumors, with a retention time of up to 48 h. Furthermore, as part of an antitumor PDT, low dose 1-PG (2 mg of Pc 1 equivalent/kg) induced a greater tumor volume reduction (-74 ± 5%) when compared to high dose ZnPc (8 mg/kg, -50 ± 12%). At higher treatment doses (8 mg of Pc 1 equivalent/kg), 1-PG reduced tumor volume maximally (-91 ± 6%) and suppressed tumor size to a minimal level for up to 15 days. The kidney, liver, and lungs of the mice treated with 1-PG (both low and high doses) were free from 4T1 tumor metastasis at the end of the study. Telemetry-spectral-echocardiography studies also revealed that PGA (65 mg/kg) produced insignificant changes to the cardiovascular physiology of Wistar-Kyoto rats when administered in vivo. Results indicate that PGA displays an excellent cardiovascular safety profile, underlining its suitability for application as a nanodrug carrier in vivo. These current findings indicate the potential of 1-PG as a useful photosensitizer candidate for clinical PDT.

Depletion of CD206+Tumour Macrophages via a Peptide-Targeted Star-Shaped Polyglutamate Inhibits Tumourigenesis and Metastatic Dissemination in Breast Cancer Models

“…route, which, barring the case of intraperitoneal chemotherapy, represents a more clinically translatable route to deliver cancer therapies. In the OximUNO system, drug release studies revealed only 15% DOX release, which agrees with our previous studies 48,50 but suggests room for improvement, which may come from using longer polymer-drug linkers such as EMCH (N-ε-maleimidocaproic acid hydrazide) moiety 48,50 or from the use of external triggers [83][84][85] . Unexpectedly, we failed to observe a significant increase in DOX release in the presence of cathepsin B with respect to the hydrolytic conditions; we hypothesise that the nanoconjugate conformation slows down proteolytic degradation, hampering in vitro quantification within the studied timeframe 47 .…”

“…Beyond TAM depletion, we show that St-PGA-mUNO represents an attractive platform to carry additional therapeutic payloads other than DOX, which could include M2M1 polarising agents such as TLR7 agonists 44,91 , beta-emitting radiotherapeutic agents such as dodecanetetraacetic acid-chelated 177 Lu 92 , or photosensitisers used in photodynamic therapy [83][84][85] . We also envisage the combination of TAM-depletion via OximUNO administration together with current chemotherapy regimens to prevent dissemination and relapse, or the use of OximUNO prior to surgery, i.e., as neoadjuvant chemotherapy Taking OximUNO as a proof-of-concept, our data support the peptide-targeted St-PGA design reported here as a new targeted nanosystem that could target other receptors by exchanging the targeting peptide.…”

“…Beyond TAM depletion, we show that St-PGA-mUNO represents an attractive platform to carry additional therapeutic payloads other than DOX, which could include M2M1 polarising agents such as TLR7 agonists 44,92 , beta-emitting radiotherapeutic agents such as dodecanetetraacetic acid-chelated 177 Lu 93 , or photosensitisers used in photodynamic therapy [84][85][86] . We also envisage the combination of TAM-depletion via OximUNO administration together with current chemotherapy regimens to prevent dissemination and relapse.…”

Recent Progress in Phthalocyanine-Polymeric Nanoparticle Delivery Systems for Cancer Photodynamic Therapy

“…Recently, a series of NIR-activatable nanocarriers based poly-L-glutamic acid with Pc conjugates in a side chain has been reported for cancer PDT [ 147 , 148 ]. These nanosystems possessed an excellent light-dark toxicity ratio compared to free ZnPc.…”

Degradable Bottlebrush Polypeptides and the Impact of their Architecture on Cell Uptake, Pharmacokinetics, and Biodistribution In Vivo

“…[32] These structures, alongside their linear analogues, have been broadly investigated for various applications in biomedicine. [33][34][35][36] Nevertheless, the MW of the star-shaped PGAs is still limited in size, in this case by the small number of arms. Recently, bottlebrush-type poly(norbornene)-graft-PGA has been reported.…”