Cationic Polyporphyrins as siRNA Delivery Vectors for Photodynamic and Gene Synergistic Anticancer Therapy

Abstract

Successful gene therapy is highly dependent on the efficiency of gene delivery, which is mostly achieved by the carrier. Current gene carriers are generally nontherapeutic and take over most of the proportion in the delivery systems. Therefore, a library of polymerized and cationic photosensitive drugs (polyphotosensitizers, pPSs) with HIF-1α siRNA delivery capability is constructed to realize using “drug” to deliver “gene”. The pPS component acts as both a therapeutic carrier for intracellular HIF-1α siRNA delivery and a photosensitive drug with photodynamic therapy (PDT). A reactive oxygen species (ROS)-cleavable linker is used to polymerize PS, allowing the successful segregation of PS monomers in space, avoiding the undesired aggregation-caused quenching (ACQ) effect and enhancing the in vitro and in vivo PDT effect. The complexes formed by pPSs and HIF-1α siRNA exhibited desired siRNA condensation and serum stability at the optimal conditions (pPSs with guanidines/siRNA weight ratio of 15), efficient intracellular internalization, and gene-silencing efficiency (60%) compared with commercial available transfection reagents (40%), as well as synergistic in vitro and in vivo phototoxicity for the combination PDT–gene therapy toward cancer treatment. This study provides a promising paradigm for the design of both the gene delivery carrier and the photosensitizer, as well as for broad utilities in the combination therapy toward cancer treatment.

Codelivery of High-Molecular-Weight Poly-porphyrins and HIF-1α Inhibitors for In Vivo Synergistic Anticancer Therapy

“…For example, porphyrin and its derivatives were encapsulated into polymeric micelles to construct nanoparticles, thus improving the hydrophilicity of porphyrin photosensitizers and achieving long-term in vivo circulation performance. − The polymeric micelles could be delivered to tumor sites through both the EPR effect and active targeting via the introduction of the targeting groups. − Recently, both linear and cross-linked poly-porphyrins connected by flexible chains have been reported by our group to successfully avoid the ACQ effect, and higher molecular weight ( M w ) featured better singlet oxygen generation ability. However, limited by the polymerization methods and the reactivity of porphyrin monomers, M w values of the poly-porphyrins were usually below 10 kDa, which hindered the further improvement of the singlet oxygen generation ability. − Moreover, oxygen was continuously consumed during PDT treatment, which inevitably resulted in tumor hypoxia. − Various signal factors, such as hypoxia-inducible factor-1α (HIF-1α), could be upregulated under hypoxia to promote angiogenesis, which would eventually cause tumor recurrence and metastasis. − Therefore, inhibiting the expression of HIF-1α during PDT is a highly promising and efficient approach to reverse hypoxia-mediated tumor resistance and overcome the restriction of PDT treatment.…”

Nanodelivery Systems Delivering Hypoxia-Inducible Factor-1 Alpha Short Interfering RNA and Antisense Oligonucleotide for Cancer Treatment

“…Downregulated HIF-1 alpha expression, which was partly generated by PDT, enhanced the PDT therapy. A 2 B 2 -type porphyrins were polymerized by a reactive oxygen species cleavable linker thioktal to form cationic polyporphyrins, which acted as both delivery carriers for HIF-1 alpha siRNA and photosensitive agent for PDT (Zheng et al, 2021). The polyphotosensitizer based gene nanocarriers, which can simultaneously impart photosensitizer with gene delivery capability and improve PDT effect through the silence of HIF-1 alpha exhibited efficient gene-silencing efficiency and synergistic anticancer potency for the combined PDT and gene therapy.…”

Cancer-Cell-Biomimetic Carbazole-Based AIE Nanoplatform for Targeted Phototheranostics of Lung Cancer

“…For early stage NSCLC, PDT is mainly used to treat endobronchial tumors, and for advanced or metastatic NSCLC and SCLC, PDT is mainly employed to alleviate symptoms from obstructing endobronchial lesions . However, most conventional PSs face the problem of aggregation-caused quenching (ACQ), for which both the fluorescence brightness and PDT effect are seriously hindered in the aggregate state. , In 2001, Tang et al first coined the aggregation-induced emission (AIE) concept, which represents a promising solution for the ACQ problem as both the emission and PDT properties of AIE luminogens (AIEgens) can be boosted in aggregate form. − Thus, AIEgen-based PSs hold great promise for PDT applications, especially in aggregate forms such as nanoparticles (NPs). − Tetraphenyl ethylene (TPE) is the most widely used building block for constructing AIEgens. − Although effective, TPE still faces some obstacles. For example, the highly twisted structure of TPE leads to a weak absorption capability (the absorption coefficients of TPE-based AIEgens are usually lower than 1.5 × 10 4 M –1 cm –1 ), and the weak electron-donating ability usually results in a short response wavelength. , Therefore, the development of new AIEgens with strong absorption ability and bright fluorescence in the deep red and near-infrared (NIR) region as well as a potent PDT property is highly desirable.…”

“…21 conventional PSs face the problem of aggregation-caused quenching (ACQ), for which both the fluorescence brightness and PDT effect are seriously hindered in the aggregate state. 22,23 In 2001, Tang et al first coined the aggregationinduced emission (AIE) concept, which represents a promising solution for the ACQ problem as both the emission and PDT properties of AIE luminogens (AIEgens) can be boosted in aggregate form. 24−26 Thus, AIEgen-based PSs hold great promise for PDT applications, especially in aggregate forms such as nanoparticles (NPs).…”