RESUMO
The purpose of this study is to evaluate the improved method of arterial infusion therapy of SMANCS (SX) with lipiodol under the angiotensin-induced hypertensive state for various difficult-to-treat solid tumors. Most patients were unresectable with no other therapeutic options, recurrence after resection, or patients do not respond to common treatments. The new method utilizes angiotensin II (AT) to induce hypertension (e.g. approximately 15-30 mmHg above norm) for 15-20 min. This method was successfully applied to metastatic liver cancer, cholangiocarcinoma, massive renal cell carcinoma, pancreatic and other abdominal solid cancers. This AT-induced hypertension resulted in remarkably enhanced tumor delivery accompanied by improved therapeutic response, and a shorter time to achieve 50% regression of tumor size with least toxicity. We demonstrated clinically herein improved therapy for various advanced solid tumors with SX by elevating the tumor blood flow selectively. This is the first clinical proof that modulations of vascular pathophysiology can uniquely accomplish enhanced tumor selective delivery of polymeric drugs and thus yielded better clinical outcome.
Assuntos
Angiotensina II/administração & dosagem , Antineoplásicos/administração & dosagem , Pressão Sanguínea/efeitos dos fármacos , Hipertensão/induzido quimicamente , Anidridos Maleicos/administração & dosagem , Neoplasias/irrigação sanguínea , Neoplasias/tratamento farmacológico , Poliestirenos/administração & dosagem , Vasoconstritores/administração & dosagem , Zinostatina/análogos & derivados , Adenocarcinoma/tratamento farmacológico , Adulto , Idoso , Carcinoma de Células Renais/tratamento farmacológico , Colangiocarcinoma/tratamento farmacológico , Sistemas de Liberação de Medicamentos , Feminino , Humanos , Infusões Intravenosas , Japão , Neoplasias Renais/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasias/patologia , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Pancreáticas/tratamento farmacológico , Zinostatina/administração & dosagemRESUMO
The copolymer of styrene-maleic acid (SMA) was used to construct micelles containing pirarubicin (4'-O-tetrahydropyranyladriamycin, or THP) as a new anticancer drug formulation. The procedure for the preparation of the micelles was simple, the component consisting of only SMA and pirarubicin in a noncovalent association, possibly by hydrophobic interaction between the styrene portion of SMA and pirarubicin chromophore. This method ensures more than 80% recovery of pirarubicin by weight, and 60% of drug loading (by weight) was achieved. The micelles obtained (SMA-THP) showed high solubility in water and a constant pirarubicin release rate of about 3-4%/day in vitro. SMA-THP micelles had an average molecular size of about 34 kDa according to gel chromatography; this size is a marked increase from the 627.6 Da of free THP, which suggests the formation of a micellar structure. When albumin was added, the molecular size of the micelles increased to about 94 kDa, which indicates binding to albumin, a unique characteristic of SMA. SMA-THP micelle preparation had a cytotoxic effect (93-101%) on MCF-7 breast cancer cells and SW480 human colon cancer cells in vitro that was comparable to that of free THP. An in vivo assay of SMA-THP at doses of 20 mg/kg in ddY mice bearing S-180 tumor revealed complete tumor eradication in 100% of tested animals. Mice survived for more than 1 year after treatment with micellar drug doses as high as 100 mg/kg pirarubicin equivalent. This marked antitumor activity can be attributed to the enhanced permeability and retention (EPR) effect of macromolecular drugs seen in solid tumors, which enables selective delivery of drugs to tumor and thus much fewer side effects. Complete blood counts, liver function test, and cardiac histology showed no sign of adverse effects for intravenous doses of the micellar preparation. These data thus suggest that intravenous administration of the SMA-THP micellar formulation can enhance the therapeutic effect of pirarubicin more than 50-fold.
Assuntos
Doxorrubicina/análogos & derivados , Doxorrubicina/química , Sistemas de Liberação de Medicamentos , Maleatos/química , Neoplasias/tratamento farmacológico , Poliestirenos/química , Animais , Doxorrubicina/administração & dosagem , Doxorrubicina/uso terapêutico , Endocárdio/ultraestrutura , Contagem de Eritrócitos , Humanos , Infusões Intravenosas , Testes de Função Hepática , Maleatos/administração & dosagem , Maleatos/uso terapêutico , Camundongos , Micelas , Peso Molecular , Poliestirenos/administração & dosagem , Poliestirenos/uso terapêutico , Solubilidade , Fatores de Tempo , Testes de Toxicidade , Células Tumorais CultivadasRESUMO
Macromolecular drugs (also referred to as polymeric drugs) are a diverse group of drugs including polymer-conjugated drugs, polymeric micelles, liposomal drugs and solid phase depot formulations of various agents. In this review we will consider only water-soluble macromolecular drugs. In common, such drugs have high molecular weights, more than 40 kDa, which enables them to overcome renal excretion. Consequently, this group of drugs can attain prolonged plasma or local half-lives. The prolonged circulating time of these macromolecules enables them to utilise the vascular abnormalities of solid tumour tissues, a phenomenon called the enhanced permeability and retention (EPR) effect. The EPR effect facilitates extravasation of polymeric drugs more selectively at tumour tissues, and this selective targeting to solid tumour tissues may lead to superior therapeutic benefits with fewer systemic adverse effects. This contrasts with conventional low-molecular-weight drugs, where intratumour concentration diminishes rapidly in parallel with plasma concentration. The EPR effect is also operative in inflammatory tissues, which justifies the development and use of this class of drugs in infectious and inflammatory conditions. At the present time, several polymeric drugs have been approved by regulatory agencies. These include zinostatin stimalamer (copolymer styrene maleic acid-conjugated neocarzinostatin, or SMANCS) and polyethyleneglycol-conjugated interferon-alpha-2a. This article discusses these and other polymeric drugs in the setting of targeting to solid tumours.