Self-assembled multifunctional nanotheranostics against circulating tumor clusters in metastatic breast cancer

Circulating tumor clusters(CTC)disseminating from the primary tumor are responsible for secondary tumor formation where the conventional treatments such as chemotherapy and radiotherapy does not prevent the metastasis at locally advanced stage of breast cancer.In this study,a smart nanotheranostic system has been developed to track and eliminate the CTCs before it can colonize at a new site,which would reduce metastatic progression and increase the five-year survival rate of the breast cancer patients.Targeted multiresponsive(magnetic hyperthermia and pH)nanomicelles incorporated with NIR fluorescent superparamagnetic iron oxide nanoparticles were developed based on self-assembly for dual modal imaging and dual toxicity for spontaneous killing of CTCs in blood stream.A heterogenous tumor clusters model was developed to mimic the CTCs isolated from breast cancer patients.The nanotheranostic system was further evaluated for the targeting property,drug release kinetics,hyperthermia and cytotoxicity against developed CTC model in vitro.In vivo model in BALB/c mice equivalent to stageⅢandⅣhuman metastatic breast cancer was developed to evaluate the biodistribution and therapeutic efficacy of micellar nanotheranostic system.Reduced CTCs in blood stream and low distant organ metastasis after treatment with the nanotheranostic system demonstrates its potential to capture and kill the CTCs that minimize the secondary tumor formation at distant sites.

Poly(1-vinylimidazole) Prospects in Gene Delivery

Polymeric amines are being studied intensively as components of systems for gene delivery in genetic engineering and gene therapy of genetic disorders, including cancer. Despite remarkable achievements in the field, polymeric amines, such as polyethyleneimine, show some disadvantages. Strong interaction between the amine-containing polymer and nucleic acid hampers the release of nucleic acid in the cell cytoplasm. Amine groups can interact with the cell membrane which results in cell death. These limitations of polymeric amines stimulated an investigation of new structures for gene delivery. Imidazole-containing polymers have attracted attention as lesser basic substances, while they are able to interact with polymeric acids. Further development of imidazole-based gene delivery agents requires knowledge about some fundamental aspects of interaction between nucleic acids, and polymeric imidazoles. In this work, we studied the complexation of poly(1-vinylimidazole) and oligomeric DNA. We found that the number of active sites capable of binding with negatively charged phosphate groups is comparable with the number of protonated imidazole units in the case of high molecular weight polymer. The increase in polymer charge by 1-bromopropane quaternizating 1%?5% imidazole units or by decreasing the pH to 6.5?7 considerably increased the ability of poly(1-vinylimidazole) to interact with oligonucleotides. The pH sensitivity of this interaction is interesting for cancer gene therapy because the tumours have a lowered intercellular pH (stable oligonucleotide complex) and a higher extracellular pH which can lead to complex dissociation. Minimal critical length for complexation of quaternized poly(1-vinylimidazole) and DNA is below eight units which corresponds to polymers with amine groups. Fluorescence-tagged poly(1-vinylimidazole) samples were obtained and their potential for monitoring the polymer and polymer-oligonucleotide complex internalization into living cells was demonstrated.

Bioinspired Water-soluble Polymers with Grafted Polyamine Chains： Synthesis and Complexation with Oligonucleotides

The siliceous frustules of diatom algae contain complex proteins known as silaffins, which consist of a peptide chain with grafted polyamine chains. These polyamines contain twenty or more nitrogen atoms with trimethylene groups between the nitrogens. We synthesized a set of polymers containing grafted long-chain polyamine fragments by using acryloyl chloride （ACh） polymers and activated acrylic acid copolymers as the starting materials. The new polymers contained 0.05 mol%-3.2 mol% of polyamine chains, which corresponded to 0.06-3.56 mmol·g- 1 amine groups. The new amine-containing polymers formed complexes with short （19-21-mer） deoxyribonucleic acid （DNA） and ribonucleic acid （RNA） strands, and these complexes penetrated into model yeast cells and A549 lung cancer cell. This study demonstrates the potential of these species based on long-chain polyamines to serve as novel gene delivery systems.