Nanotechnology-based intelligent drug design for cancer metastasis treatment

Yu Gao, Jingjing Xie, Haijun Chen, Songen Gu, Rongli Zhaoa, Jingwei Shao, Lee Jia

  • Current cancer treatment options, such as radiation therapy and surgery can be effective during the primary stages of cancer. However, once the cancer spreads or metastasizes, these treatments may not be the best choice for the patient.
  • Chemotherapy and cytoxic drugs are also cancer treatment options that are used as total body treatments. On the contrary, these treatments have negative side effects, including toxic exposure to normal, healthy cells, lack of drug concentrations at tumors or cancerous cells, and the development of multidrug resistance.
  • Nanomedicine focuses on applying nanotechnology to medicine for the diagnosis, prevention, detection, and treatment of disease.
  • Specifically, nanotechnology has been utilized for the development of a targeted drug delivery system (TDDS). A targeted drug delivery system would allow for the delivery of therapeutic drugs to the site of injury or illness.
  • Potential benefits of a TDDS include: protecting the therapeutic drug from degrading, modifying the pharmacokinetic and tissue distribution profile, in order to increase the drug distribution in the tumor, reducing the toxic exposure to normal cells, and increasing the cellular absorption of the treatment in cancer cells.
    • Pharmacokinetics is the study of the bodily absorption, distribution, metabolism, and excretion of drugs, (pharmacokinetics).
  • Many different types of nanocarriers have been synthesized. They include: dendrimers, liposomes, solid lipid nanoparticles, polymersomes, micelles, nanoemulsions, ect.
    • Lipid-based nanoparticles have been found to have tremendous potential to the TDDS because of their biocompatibility, biodegradability, low chance of inducing an immune response, and ability to transport both hydrophilic (water loving/polar) and hydrophobic drugs, (water fearing/nonpolar).
  • Polymer-based nanoparticles have shown to have a great potential for treating disease or repairing tissues, especially in cancer treatment, because of their “small size, biocompatibility, biodegradability, prolonged circulation time in the blood stream, enhanced drug loading capacity, and easy chemical modification or surface functionality,” (Gao).
  • Organic nanoparticles, including liposomes, dendrimers, and polymeric micelles, have been used in cancer diagnosis and therapy.
  • Nanomedicine has a lot of potential for “multimodality treatment,” (Gao).
    • Nanoparticulate drug delivery systems have been found to have more advantages than conventional drug delivery systems because of the ability to physically blend multiple drugs together. These advantages include: “improved solubility and bioavailability, lack of elimination by macrophages and prolonged drug circulation half-life, increased tumor site accumulation by passive or active targeting, efficient internalization with the mechanism of endocytosis, controlled pharmocokinetics of each drug, resulting in enhanced drug efficacy and reduced side effects,” (Gao).

Synthesis of a novel zwitterionic biodegradable poly (α,β,L-aspartic acid) derivative with some L-histidine side-residues and its resistance to non-specific protein adsorption

Xiaojuan Wanga, Guolin Wua, Caicai Lua, Yinong Wanga, Yunge Fana, Hui Gaob, Jianbiao Ma

  • “Protein adsorption is the first response from the human body to foreign materials exposed to the physical environment,” (Wang). Most protein adsorption, however, is harmful to the biomaterials or implants that are inserted into the body. As a result of this protein adsorption, unwanted bioresponses, like coagulation and thrombosis, may be induced.
    • Coagulation is the clotting of blood, and thrombosis is the formation of a blood clot either in the heart or in a blood vessel, (“thrombosis”).
  • Due to the uniform mixture of balanced charges on the their molecular surface, zwitterionic polymers are known to effectively decrease protein adsorption.
    • Zwitterions are large molecules that have a net positive charge on one side of the molecule and a net negative charge on the other side of the molecule, (“liquid”).
  • Purpose of Study: To investigate the zwitterionic properties of the zwitterionic derivative of poly (α,β,L-apartic acid), and its ability resist protein adsorption, (Wang).
  • Methods: Researchers prepared a zwitterionic  polymer, poly (α,β,L-apartic acid). Nuclear magnetic resonance (NMR) Spectroscopy was then performed on the polymer, and the buffering capacity of the polymer was also recorded. Silica wafers were coated in the zwitterionic polymer and then incubated in solution of fibronogen. (Fibronogen is a protein, whose adsorption onto medical devices has yielded undesirable bioresponses.) The researchers determined the amount of fibronogen adsorbed by the silica wafers by measuring the concentration of fibronogen before and after the wafers were incubated in the fibronogen solution. Lastly, the adsorption capacity of the silica wafers was determined using the following equation: q=(Ci-Cf)V/s.
  • Results/Conclusion: The adsorption of fibronogen of the silica wafers was found to be inhibited by the zwitterionic polymer coating. This result suggests that coating medical devices with the zwitterionic polymer may be a possible solution to the negative bioresponses initiated by medical devices, (Wang).

 

Drug eluting stents: Current status and new developments

Gökhan Ertaş, Heleen Van Beusekom

  •  The two main issues with coronary artery stents are that they cause restenosis and stent thrombosis.
    • “Restenosis is the re-occurrence of the narrowing of the diameter of a blood vessel or heart valve after it has been treated (as by balloon angioplasty or valvuloplasty) with apparent success,” (stenosis, restenosis).
    • Thrombosis is the formation of a blood clot either in the heart or in a blood vessel, (“thrombosis”).
  • In balloon angioplasty, the rate of restenosis was found to be between 40%-60%
  • Stent thrombosis was found to be common within the first three weeks after the implantation of a bare metal stent (BMS).
  • Fortunately, advances in antiplatelet therapy have nearly eliminated the rate of stent thrombosis, following the implantation of BMS implants. However, despite this good news, the rate of stent restenosis is still high, and therefore, still an obstacle biomedical engineers must face.
  • Restenosis can be explained by: early elastic recoil, late vessel remodeling, and neointima formation.
    • “Neointima is a new or thickened layer of the innermost coat of an artery,” (intima, neointima).
    • Furthermore, neointima formation results from a series of molecular and cellular events that are initiated by platelet activation, leukocyte, (white blood cell), infiltration, the proliferation of smooth muscle cells, and the production of cellular matrix materials.
  • Drug eluting stents (DES) are stents that target and help inhibit smooth muscle growth.
    • Drugs that have anti-inflammatory, anti-thrombogenic, anti-proliferative, immunosuppressive properties are used in the drug eluting stents, in order to decrease the rate of restenosis.
  • Therefore, due to the use of of drug eluting stents, the rate of restenosis has started to decrease.
  • Future studies, therefore, seek to improve the long-term effectiveness of drug eluting stents by making more applicable for temporary use by making them completely degradable, (Ertas).

 

 Modular Tapered Implants for Severe Femoral Bone Loss in THA: Reliable Osseointegration but Frequent Complications

Nicholas M. Brown, Matthew Tetreault, Cara A. Cipriano, Craig J. Della Valle, Wayne Paprosky1 and Scott Sporer

  • Revision total hip arthroplasty, (THA), in a patient  with femoral bone loss, has a variety of treatments options. However, many of these treatment options are associated with complications, like thigh pain, stress shielding, and intraoperative, (post operative fractures).
  • Modular tapered titanium stems have been deemed an alternative treatment option for more complex femoral abnormalities, due to the tapered, distal geometry of the implants.
  • Purpose: “To determine, at minimum 2-year followup, the survivorship of modular tapered implants used in the setting of severe femoral bone loss; radiographic evidence of osseointegration of these stems; and Harris hip scores, complications, and reoperations associated with the use of these stems for complex femoral revisions,” (Brown).
  • Methods: Arthroplasty surgeons performed 58 revisions of total hip arthroplasty on patients with Paprosky Type IIIB and IV femurs. (Paprosky Type IIIB and IV femurs are femurs that have undergone severe bone loss.) All 58 patients received revision of THA using modular tapered femoral implants. 41 patients received a ZMR stem prosthesis, 14 patients received a Restoration stem prosthesis, and 3 patients received the MP reconstruction stem. The researchers followed-up with the patients after a minimum of two year. During the follow-up, the patients were evaluated according to the Harris hip score, asked about thigh pain, and evaluated for other complications.
  • Results/Conclusion: After the revisions were completed, the number of patients experiencing complications decreased from 15 to 10. In conclusion, it has been found that the modular tapered stems provided a low likelihood of revision, after a minimum of two years. However, larger-scale, long-term studies are necessary in order to accurately test the efficacy of the implants, (Brown).

 

Sources

Brown N, Tetreault M, Cipriano C, Della Valle C, Paprosky W, Sporer S. Modular Tapered Implants for Severe Femoral Bone Loss in THA: Reliable Osseointegration but Frequent Complications. Clinical Orthopaedics & Related Research [serial online]. February 2015;473(2):555-560. Available from: Academic Search Premier, Ipswich, MA. Accessed April 30, 2015.

Ertaş G, Van Beusekom H. Drug eluting stents: Current status and new developments. Anatolian Journal Of Cardiology / Anadolu Kardiyoloji Dergisi [serial online]. December 2012;12(8):676-683. Available from: Academic Search Premier, Ipswich, MA. Accessed April 30, 2015.

Gao Y, Xie J, Jia L, et al. Nanotechnology-based intelligent drug design for cancer metastasis treatment. Biotechnology Advances [serial online]. July 2014;32(4):761-777. Available from: MEDLINE, Ipswich, MA. Accessed April 29, 2015.

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Pharmacokinetics. (2015). In Medline Plus. Bethesda, MD: U.S. National Library of Medicine.

Restenosis. (2015). In Medline Plus. Bethesda, MD: U.S. National Library of Medicine.

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Wang X, Wu G, Ma J, et al. Synthesis of a novel zwitterionic biodegradable poly (alpha,beta-L-aspartic acid) derivative with some L-histidine side-residues and its resistance to non-specific protein adsorption. Colloids And Surfaces B-Biointerfaces [serial online]. n.d.;86(1):237-241. Available from: Science Citation Index, Ipswich, MA. Accessed April 29, 2015.