Solid phase synthesis of peptide–siRNA conjugates containing disulfde bond unit

A disulfide-modified nucleoside was designed and synthesized. After loading the modified nucleoside on controlled pore glass （CPG）, solid phase synthesis strategy was used to prepare peptide-oligonucleotide conjugates （N-3＇） containing disulfide bond unit. The 3＇-sense strand peptide-siRNA conjugate （VII） maintained good gene silencing activity, while that of the 3＇-antisense strand conjugate decreased somewhat. And the sense strand off-target effect of VII decreased remarkably.

Serum stability enhancement of siRNA caused by peptide conjugation at 3'-terminus of sense strand

RNA interference has been widely used for gene therapy of various infectious diseases and malignant tumors. However, its poor stability in serum has limited further clinic application. Here, we found that stability of siRNA in serum enhanced obviously when 3′-terminus of sense strand （siRNA-pS） was conjugated with peptide, while same conjugation at 3′-terminus of antisense strand brought no such effects. And it was also found that only the peptide residue in siRNA-pS could be cut off by RNase A. All these results indicated that nucleases in serum prefer to invade siRNA duplex through the 3′-end of sense strand.

In vitro and in vivo evaluation of improved EGFR targeting peptide-conjugated phthalocyanine photosensitizers for tumor photodynamic therapy

Phthalocyanine（Pc） is one of the most promising photosensitizer candidates because of its strong absorption（extinction coefficient ε > 10;LmoI;cm;） at long wavelengths and strong singlet oxygen generation abilities（a singlet oxygen quantum yield of approximately 50%）. However, low tumor targeting, low water solubility and a high tendency to aggregate appear to significantly restrict the compound’s application in tumor treatment. Conjugating Pc with peptide ligands could be a useful strategy for alleviating these problems. Here, to further optimize the structures of peptide-conjugated zinc Pcs for PDT therapy, we finely tuned the hydrophilicity of the modified Pc aromatic macrocycle with varied length of polyethylene glycol（PEG） and added an extra PEG linker and an extra glutamic acid between the Pc ring and the peptide ligand to reduce the influence of the ligand on the Pc aromatic ring.Among the synthesized conjugates, Pc-3 showed greatly improved targeting towards tumors and abolished inoculated tumors with only a single PDT treatment in a subcutaneous xenograft tumor model,making this approach a promising therapeutic agent for the treatment of cancer.

Carbon nanotubes targeted to the tumor microenvironment inhibit metastasis in a preclinical model of melanoma

Despite notable progress in cancer therapy,metastatic diseases continue to be the primary cause of cancer-related mortality.Multi-walled carbon nanotubes(MWCNTs)can enter tissues and cells and interfere with the dynamics of the cytoskeletal nanofilaments biomimetically.This endows them with intrinsic anti-tumoral effects comparable to those of microtubule-binding chemotherapies such as Taxol®.In this study,our focus was on exploring the potential of oxidized MWCNTs in selectively targeting the vascular endothelial growth factor receptor(VEGFR).Our objective was to evaluate their effectiveness in inhibiting metastatic growth by inducing anti-proliferative,anti-migratory,and cytotoxic effects on both cancer and tumor microenvironment cells.Our findings demonstrated a significant reduction of over 80%in malignant melanoma lung metastases and a substantial enhancement in overall animal welfare following intravenous administration of the targeted biodegradable MWCNTs.Furthermore,the combination of these nanomaterials with the conventional chemotherapy agent Taxol®yielded a remarkable 90%increase in the antimetastatic effect.These results highlight the promising potential of this combined therapeutic approach against metastatic disease and are of paramount importance as metastasis is responsible for nearly 60,000 deaths each year.