Clinical benefit of this combination therapy was noted in more than 40% of all patients in the original study. The combination of paclitaxel and carboplatin is used as second-line therapy for patients who suffer from disease progression while receiving DTIC treatment. Dacarbazine (DTIC), a widely used chemotherapeutic agent for treatment of metastatic melanoma, shows transient efficacy in most patients, however, only 1–2% of patients achieve a durable long-term response to this therapy. Unfortunately, the survival of patients with advanced metastatic melanoma has not been significantly improved by current Food and Drug Administration (FDA)-approved systemic chemotherapies. The median overall survival time of patients suffering from metastatic melanoma is less than one year, and only about 10% of these patients survive more than 5 years after diagnosis.
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Malignant melanoma is the most invasive form of skin cancer with high metastatic propensity, typically metastasizing to the lymph nodes, lungs, liver, brain and heart at late stage of melanoma. The polymer-drug conjugate market is currently becoming well-established with several commercialized products available for a wide range of disease states, such as Adynovate by Baxalta, Movantik™ by AstraZeneca, Oncospar® by Enzon Pharmaceuticals, Plegridy® by Biogen, etc. Unlike physically drug encapsulation into nanoparticles and micelles, covalent drug conjugation to polymers achieves enhanced drug payload and prevents premature drug release, thereby decreasing undesired toxicities compared to physically drug-encapsulated liposomes, nanoparticles and micelles. Advantages of conjugates over their corresponding parent drugs include: 1) increased aqueous solubility of hydrophobic drugs 2) prolonged blood circulation time 3) enhanced bioavailability 4) increased protection of drugs from degradation 5) increased tumor accumulation either due to enhanced permeability and retention (EPR) effect or tunable targeting moieties. Since then, the field of polymer-drug conjugates started a new era of drug delivery and has been growing fast. Polymer-drug conjugates debuted in 1955, and in the mid-1970s Ringsdorf proposed the idea of conjugating therapeutic agents to water soluble polymers. A large amount of pioneering research has highlighted applications of micelles, nanoparticles, liposomes, polymersomes, nanogels and dendrimers as nanocarriers of low molecular-weight drugs, oligonucleotides and genes. Over the past several decades, the development of nanomedicines has been driven by the increasing demands of delivering therapeutic agents to disease sites efficiently.
In conclusion, P-SMART, a novel polymer-microtubule destabilizer conjugate, has the potential to treat metastatic melanoma. P-SMART treatment resulted in significant inhibition of tumor growth and prolonged mouse median survival. We established a model of metastatic melanoma to the lung in C57/BL6 albino mice to determine in vivo efficacy of P-SMART and SMART-OH at the dose of 20 mg/kg. In addition, P-SMART treatment led to cell cycle arrest at G2/M phase and cell accumulation in sub-G1 phase. Similar to its parent drug, P-SMART showed significant anticancer activity against melanoma cells in cytotoxicity, colony formation, and cell invasion studies. To solve this problem and also to increase circulation time, we synthesized a new SMART analogue, SMART-OH, and its polymer-drug conjugate, methoxy-poly (ethylene glycol)-block-poly (2-methyl-2-carboxyl-propylene carbonate-graft-SMART-graft-dodecanol) (abbreviated as P-SMART), with 14.3☒.8% drug payload of SMART-OH. Due to poor water solubility of SMART compounds, co-solvent delivery is required for their systemic administration, which is usually associated with hepatotoxicity, nephrotoxicity and hemolysis.
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We synthesized a series of microtubule destabilizers, substituted methoxybenzoylary-thiazole (SMART) compounds, which inhibited tubulin polymerization and effectively circumvented MDR.
Systemic chemotherapy remains the mainstay of treatment however, the development of multidrug resistance (MDR) restricts the efficacy of current chemotherapeutic drugs. It is highly metastatic, migrating through lymph nodes to distant sites of the body, especially to lungs, liver and brain. Melanoma is the most aggressive type of skin cancer.
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