Self-Assembly Of Retinoid Nanoparticles For Melanoma Therapy

Abstract

Background: Amphiphilic fusion drugs are covalent conjugates of a lipophilic drug and a hydrophilic drug or their active fragments. These carrier-free self-assembly nanomaterials are helpful to co-deliver two synergic drugs to the same site regardless of pharmacokinetic properties of individual drugs. Retinoic hydroxamic acid (RHA) is a "fusion drug" of all-trans retinoic acid (ATRA) and vorinostat, a histone deacetylase (HDAC) inhibitor showing synergic effect with ATRA on cancer therapy. Although RHA was synthesized in 2005, its nanoscale self-assembly property, anticancer activity, and possible related mechanism are still unclear.

Methods: RHA nanoparticles were observed under transmission electron microscope (TEM). Both in vitro cell viability, colony formation assay, and in vivo xenograft mouse tumor model were employed here to study anticancer activity of RHA nanoparticles. The putative synergic anticancer mechanism of activating retinoic acid receptor (RAR) and inhibiting HDAC were investigated via receptor inhibitor rescue assay and in vitro enzyme activity assay, respectively.

Results: RHA could form nanoparticle formation by self-assembly and abrogates growth of several solid tumor cell lines even after RHA nanoparticles' washout. However, opposite to our initial hypothesis, pre-treating the melanoma cells with RAR antagonists showed no impact on inhibitory effect of RHA nanoparticles, which suggested that the target of the molecule on melanoma cells is not RAR and retinoid X receptor (RXR). Importantly, RHA nanoparticles inhibited the growth of xenograft tumors without obvious impact on haematological indexes and hepatorenal function of these tumor-bearing mice.

Conclusion: Our findings demonstrate the promise of RHA nanoparticles in treating malignant melanoma tumors with high efficacy and low toxicity.

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See also:

- Official Web Site: The Di Bella Method;

- The Di Bella Method (A Fixed Part - All-Trans Retinoic Acid, Analogues and/or Derivatives - Approximately 60mg per day orally: 40mg per day Beta-Carotene/β-Carotene, 10mg per day ATRA and 10mg per day Axerophthol palmitate);

- All-Trans-Retinoic Acid (ATRA - analogues and/or derivatives) - In vitro, review and in vivo publications;

- Solution of retinoids in vitamin E in the Di Bella Method biological multitherapy;

- The Di Bella Method (A Fixed Part - Alpha tocopheryl acetate/Vitamin E, approximately 20 grams per day orally);

- Cancer and Vitamin E (analogues and/or derivatives) and cancer - In vitro, review and in vivo publications;

- The Di Bella Method (A Fixed Part - Cyclophosphamide 50mg tablets and/or Hydroxyurea 500mg tablets, one or two per day);

- Recurrent Glioblastoma Multiforme (grade IV – WHO 2007): a case of complete objective response achieved by means of the concomitant administration of Somatostatin and Octreotide – Retinoids – Vitamin E – Vitamin D3 – Vitamin C – Melatonin – D2 R agonists (Di Bella Method – DBM) associated with Temozolomide;

- The Di Bella Method DBM improved survival objective response and performance status in a retrospective observational clinical study on 23 tumours of the head and neck;

- Chronic Lymphocytic Leukemia: Long-Lasting Remission with Combination of Cyclophosphamide, Somatostatin, Bromocriptine, Retinoids, Melatonin, and ACTH;

- Somatostatin, retinoids, melatonin, vitamin D, bromocriptine, and cyclophosphamide in advanced non-small-cell lung cancer patients with low performance status;

- Somatostatin, retinoids, melatonin, vitamin D, bromocriptine, and cyclophosphamide in chemotherapy-pretreated patients with advanced lung adenocarcinoma and low performance status;

- Observations on the Report of a case of pulmonary adenocarcinoma with lymph node, hepatic and osseus metastasis;

- Neuroblastoma: Complete objective response to biological treatment;

- Cyclophosphamide plus Somatostatin, Bromocriptin, Retinoids, Melatonin and ACTH in the Treatment of Low-grade Non-Hodgkin’s Lymphomas at Advanced Stage: Results of a Phase II Trial;

- Relapse of High-Grade Non-Hodgkin’s Lymphoma After Autologous Stem Cell Transplantation: A Case Successfully Treated With Cyclophosphamide Plus Somatostatin, Bromocriptine, Melatonin, Retinoids, and ACTH;

- Low-grade Non-Hodgkin Lymphoma at Advanced Stage: A Case Successfully Treated With Cyclophosphamide Plus Somatostatin, Bromocriptine, Retinoids, and Melatonin;

- The Di Bella Method (DBM) improved survival, objective response and performance status in a retrospective observational clinical study on 55 cases of Lymphomas;

- Large B-cells Non-Hodgkin's Lymphoma, Stage IV-AE: a Case Report;

- Non-Hodgkin's Lymphoma, Stage III-B-E: a Case Report;

- Oesophageal squamocellular carcinoma: a complete and objective response;

- Congenital fibrosarcoma in complete remission with Somatostatin, Retinoids, Vitamin D3, Vitamin E, Vitamin C, Melatonin, Calcium, Chondroitin sulfate associated with low doses of Cyclophosphamide in a 14-year Follow Up.