RESUMEN
DNA- based vaccines have demonstrated the potential as a safe and effective modality. PlaCCine, a DNA-based vaccine approach described subsequently relies on a synthetic DNA delivery system and is independent of virus or device. The synthetic functionalized polymer combined with DNA demonstrated stability over 12 months at 4C and for one month at 25C. Transfection efficiency compared to naked DNA increased by 5-15-fold in murine skeletal muscle. Studies of DNA vaccines expressing spike proteins from variants D614G (pVAC15), Delta (pVAC16), or a D614G + Delta combination (pVAC17) were conducted. Mice immunized intramuscular injection (IM) with pVAC15, pVAC16 or pVAC17 formulated with functionalized polymer and adjuvant resulted in induction of spike-specific humoral and cellular responses. Antibody responses were observed after one immunization. And endpoint IgG titers increased to greater than 1x 105 two weeks after the second injection. Neutralizing antibodies as determined by a pseudovirus competition assay were observed following vaccination with pVAC15, pVAC16 or pVAC17. Spike specific T cell immune responses were also observed following vaccination and flow cytometry analysis demonstrated the cellular immune responses included both CD4 and CD8 spike specific T cells. The immune responses in vaccinated mice were maintained for up to 14 months after vaccination. In an immunization and challenge study of K18 hACE2 transgenic mice pVAC15, pVAC16 and pVAC17 induced immune responses lead to decreased lung viral loads by greater than 90 % along with improved clinical score. These findings suggest that PlaCCine DNA vaccines are effective and stable and further development against emerging SARS-CoV-2 variants is warranted.
Asunto(s)
COVID-19 , Vacunas de ADN , Ratones , Animales , Vacunas contra la COVID-19 , COVID-19/prevención & control , SARS-CoV-2 , Ratones Transgénicos , Anticuerpos Neutralizantes , ADN , Anticuerpos Antivirales , Glicoproteína de la Espiga del Coronavirus/genética , Inmunogenicidad VacunalRESUMEN
PURPOSE: To inform continued development of the novel immune agent GEN-1, we compared ovarian cancer patients' end points from a neoadjuvant single-arm phase IB study with those of similar historic clinical trial (HCT) patients who received standard neoadjuvant chemotherapy. METHODS: Applying OVATION-1 trial (ClinicalTrials.gov identifier: NCT02480374) inclusion and exclusion criteria to Medidata HCT data, we identified historical trial patients for comparison. Integrating patient-level Medidata historic trial data (N = 41) from distinct neoadjuvant ovarian phase I-III trials with patient-level OVATION-1 data (N = 18), we selected Medidata patients with similar baseline characteristics as OVATION-1 patients using propensity score methods to create an external control arm (ECA). RESULTS: Fifteen OVATION-1 patients (15 of 18, 83%) were matched to 15 (37%, 15 of 41) Medidata historical trial control patients. Matching attenuated preexisting differences in attributes between the groups. The median progression-free survival time was not reached by the OVATION-1 group and was 15.8 months (interquartile range, 11.40 months to nonestimable) for the ECA. The hazard of progression was 0.53 (95% CI, 0.16 to 1.73), favoring GEN-1 patients. Compared with ECA patients, OVATION-1 patients had more nausea, fatigue, chills, and infusion-related reactions. CONCLUSION: Comparing results of a single-arm early-phase trial to those of a rigorously matched HCT ECA yielded insights regarding comparative efficacy prior to a randomized controlled trial. The effect size estimate itself informed both the decision to continue development and the randomized phase II trial (ClinicalTrials.gov identifier: NCT03393884) sample size. The work illustrates the potential of HCT data to inform drug development.
Asunto(s)
Neoplasias Ováricas , Femenino , Humanos , Neoplasias Ováricas/tratamiento farmacológico , Supervivencia sin ProgresiónRESUMEN
PURPOSE: GEN-1 (phIL-12-005/PPC), an IL12 plasmid formulated with polyethyleneglycol-polyethyleneimine cholesterol lipopolymer, has preclinical activity when combined with platinum-taxane intravenous chemotherapy and administered intraperitoneally in epithelial ovarian cancer (EOC) models. OVATION I was a multicenter, nonrandomized, open-label phase IB trial to evaluate the safety, preliminary antitumor activity, and immunologic response to GEN-1 in combination with neoadjuvant chemotherapy (NACT) carboplatin-paclitaxel in patients with advanced EOC. PATIENTS AND METHODS: A total of 18 patients with newly diagnosed stage IIIC and IV EOC were enrolled. A standard 3+3 dose-escalation design tested four GEN-1 doses (36, 47, 61, 79 mg/m2) to determine the maximum tolerated dose and dose-limiting toxicities (DLTs). GEN-1 was administered in eight weekly intraperitoneal infusions starting at cycle 1 week 2 in combination with three 21-day cycles of NACT carboplatin AUC 6 and weekly paclitaxel 80 mg/m2. RESULTS: The most common treatment-emergent adverse events at least possibly related were nausea, fatigue, abdominal pain/cramping, anorexia, diarrhea, and vomiting. Eight patients experience grade 4 neutropenia attributed to NACT. No DLTs occurred. A total of 14 patients were evaluable for response and 12 (85.7%) had radiological response (two complete response and 10 partial response) prior to debulking; nine were R0 at debulking and one patient had complete pathologic response. IL12 and its downstream cytokine, IFNγ, increased in peritoneal washings but not as much in blood. Increased levels of myeloid dendritic cells and T-effector memory cells in peritoneal fluid, plus elevated CD8+ T cells and reduced immunosuppression within the tumor microenvironment were found. A median time to treatment failure of 18.4 months (95% confidence interval, 9.2-24.5) was observed in the intention-to-treat population. CONCLUSIONS: Adding GEN-1 to standard NACT is safe, appears active, and has an impact on the tumor microenvironment.
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Protocolos de Quimioterapia Combinada Antineoplásica , Carboplatino , Carcinoma Epitelial de Ovario , Terapia Neoadyuvante , Neoplasias Ováricas , Paclitaxel , Anciano , Femenino , Humanos , Persona de Mediana Edad , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Carboplatino/administración & dosificación , Carcinoma Epitelial de Ovario/tratamiento farmacológico , Carcinoma Epitelial de Ovario/patología , Estadificación de Neoplasias , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/patología , Paclitaxel/administración & dosificaciónRESUMEN
GEN-1 is a gene-based immunotherapy, comprising a human IL-12 gene expression plasmid and a synthetic plasmid delivery system, delivered intraperitoneally (ip.) to produce local and persistent levels of a pleiotropic immunocytokine, IL-12, at the tumor site in patients with advanced ovarian cancer. The goal of local and persistent IL-12 delivery is to remodel the highly immunosuppressive tumor microenvironment to favor immune stimulation while avoiding serious systemic toxicities, a major limitation of recombinant IL-12 therapy. Safe and sustained local production of IL-12 and related immunocytokines at the tumor site could produce potentially more favorable immunological changes in the tumor microenvironment and antitumor responses than a bolus systemic delivery of recombinant IL-12. Treatment safety, clinical benefits and biological activity of GEN-1 ip. in patients with ovarian cancer and in representative animal models are described.
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Expresión Génica , Terapia Genética , Inmunomodulación/genética , Inmunoterapia , Interleucina-12/genética , Neoplasias Ováricas/genética , Neoplasias Ováricas/terapia , Animales , Estudios Clínicos como Asunto , Terapia Combinada , Citocinas/genética , Citocinas/metabolismo , Modelos Animales de Enfermedad , Femenino , Técnicas de Transferencia de Gen , Terapia Genética/métodos , Humanos , Inmunoterapia/métodos , Interleucina-12/metabolismo , Neoplasias Ováricas/inmunología , Resultado del Tratamiento , Microambiente Tumoral/genética , Microambiente Tumoral/inmunologíaRESUMEN
OBJECTIVE: The study's purpose was to assess safety and efficacy of escalating doses of weekly GEN-1 with pegylated liposomal doxorubicin (PLD) in patients with recurrent or persistent epithelial ovarian, fallopian tube or primary peritoneal cancers (EOC). METHODS: Patients had persistent or recurrent platinum-resistant EOC. The trial was a standard 3+3 phase I dose escalation design with patients receiving intravenous PLD 40mg/m2 (dose level 1 and 2) or 50mg/m2 (dose level 3) every 28days and intraperitoneal GEN-1 at 24mg/m2 (dose level 1) or 36mg/m2 (dose level 2 and 3) on days 1, 8, 15, and 22 of a 28day cycle. Cycles were repeated every 28days until disease progression. Patients were monitored for toxicity, clinical efficacy, and evidence of systemic and intraperitoneal immunologic effect. RESULTS: Sixteen evaluable patients received a median of 4cycles (range 1-8). No dose limiting toxicities were found. The adverse side effects were 4 grade 3 anemia, 2 grade 3 abdominal pain, 7 grade 3 neutropenia, and 2 grade 4 neutropenia. A clinical benefit of 57.1% (PR=21.4%; SD=35.7%) was found in the 14 patients with measurable disease. The highest number of partial responses (28.6%) and stable disease (57.1%) were found at dose level 3. The maximum tolerated dose was not reached. Increases in IL-12, IFN-γ, and TNF-α levels were found in peritoneal fluid following GEN-1 treatment. CONCLUSIONS: GEN-1 in combination with PLD has encouraging clinical benefit and biological activity in recurrent or persistent EOC and warrants further investigation with escalating doses of GEN-1.
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Doxorrubicina/análogos & derivados , Neoplasias de las Trompas Uterinas/terapia , Terapia Genética/métodos , Interleucina-12/genética , Neoplasias Glandulares y Epiteliales/terapia , Neoplasias Ováricas/terapia , Neoplasias Peritoneales/terapia , Anciano , Antibióticos Antineoplásicos/administración & dosificación , Carcinoma Epitelial de Ovario , Supervivencia sin Enfermedad , Relación Dosis-Respuesta a Droga , Doxorrubicina/administración & dosificación , Neoplasias de las Trompas Uterinas/tratamiento farmacológico , Neoplasias de las Trompas Uterinas/genética , Femenino , Humanos , Interleucina-12/administración & dosificación , Persona de Mediana Edad , Recurrencia Local de Neoplasia/tratamiento farmacológico , Recurrencia Local de Neoplasia/genética , Neoplasias Glandulares y Epiteliales/tratamiento farmacológico , Neoplasias Glandulares y Epiteliales/genética , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/genética , Neoplasias Peritoneales/tratamiento farmacológico , Neoplasias Peritoneales/genética , Plásmidos/administración & dosificación , Plásmidos/genética , Polietilenglicoles/administración & dosificación , Polietileneimina/administración & dosificación , Polietileneimina/análogos & derivadosRESUMEN
OBJECTIVES: The primary objective of this study was to evaluate the safety and tolerability of a formulated IL-12 plasmid administered intraperitoneally (IP) in conjunction with intravenous (IV) carboplatin/docetaxel in platinum-sensitive ovarian cancer patients. METHODS: Escalating doses of IL-12 plasmid (phIL-12) formulated with the lipopolymer PEG-PEI-Cholesterol (PPC) were administered IP every 10-11 days for a total of four treatments and the highest dose was expanded to eight treatments. Patients also received IV carboplatin (AUC 5) and docetaxel (75 mg/m(2)) every 21 days. Patients were followed for safety, biological activity and antitumor activity after phIL-12/PPC treatment. RESULTS: All 13 patients enrolled in the study received both phIL-12/PPC and chemotherapy treatment. There were 49 plasmid-associated adverse events (AEs). The most common AEs were abdominal pain, transient hypotension, low grade fever, catheter site pain, chills, dysgeusia, infusion-related reaction, and nausea. These AEs appeared to be plasmid dose related. Grade 3 AEs included manageable abdominal pain and cytokine release syndrome. There were no dose limiting toxicities and the plasmid treatment did not augment the chemotherapy-associated AEs. The best overall antitumor response (17% CR, 33% PR, 42% SD and 8% PD) was typical of the patient population enrolled for the study. Translational studies showed rise in IFN-γ and TNF-α concentrations in a dose dependent manner. CONCLUSIONS: The escalating doses and cycles of intraperitoneal phIL-12/PPC when combined with carboplatin/docetaxel chemotherapy in recurrent ovarian cancer patients were well tolerated and did not appear to exacerbate the side effects or attenuate the efficacy of the chemotherapy treatment.
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Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Interleucina-12/efectos adversos , Neoplasias Glandulares y Epiteliales/tratamiento farmacológico , Neoplasias Ováricas/tratamiento farmacológico , Dolor Abdominal/inducido químicamente , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carboplatino/administración & dosificación , Carcinoma Epitelial de Ovario , Escalofríos/inducido químicamente , Docetaxel , Disgeusia/inducido químicamente , Femenino , Fiebre/inducido químicamente , Terapia Genética , Humanos , Hipotensión/inducido químicamente , Interleucina-12/administración & dosificación , Interleucina-12/genética , Persona de Mediana Edad , Náusea/inducido químicamente , Plásmidos/administración & dosificación , Taxoides/administración & dosificaciónRESUMEN
We have designed a series of versatile lipopolyamines which are amenable to chemical modification for in vivo delivery of small interfering RNA (siRNA). This report focuses on one such lipopolyamine (Staramine), its functionalized derivatives and the lipid nanocomplexes it forms with siRNA. Intravenous (i.v.) administration of Staramine/siRNA nanocomplexes modified with methoxypolyethylene glycol (mPEG) provides safe and effective delivery of siRNA and significant target gene knockdown in the lungs of normal mice, with much lower knockdown in liver, spleen, and kidney. Although siRNA delivered via Staramine is initially distributed across all these organs, the observed clearance rate from the lung tissue is considerably slower than in other tissues resulting in prolonged siRNA accumulation on the timescale of RNA interference (RNAi)-mediated transcript depletion. Complete blood count (CBC) analysis, serum chemistry analysis, and histopathology results are all consistent with minimal toxicity. An in vivo screen of mPEG modified Staramine nanocomplexes-containing siRNAs targeting lung cell-specific marker proteins reveal exclusive transfection of endothelial cells. Safe and effective delivery of siRNA to the lung with chemically versatile lipopolyamine systems provides opportunities for investigation of pulmonary cell function in vivo as well as potential treatments of pulmonary disease with RNAi-based therapeutics.
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Poliaminas Biogénicas/química , Pulmón/metabolismo , ARN Interferente Pequeño/administración & dosificación , Animales , Poliaminas Biogénicas/síntesis química , Poliaminas Biogénicas/metabolismo , Recuento de Células Sanguíneas , Femenino , Silenciador del Gen , Inyecciones Intravenosas , Pulmón/patología , Ratones , Ratones Endogámicos ICR , Ratones Transgénicos , Nanoconjugados/administración & dosificación , Nanoconjugados/efectos adversos , Nanoconjugados/química , Polietilenglicoles/química , ARN Interferente Pequeño/síntesis química , ARN Interferente Pequeño/metabolismo , Mucosa Respiratoria/efectos de los fármacos , Mucosa Respiratoria/metabolismo , TransfecciónRESUMEN
Exploitation of the RNA interference (RNAi) pathway offers the promise of new and effective therapies for a wide variety of diseases. Clinical development of new drugs based on this platform technology is still limited, however, by a lack of safe and efficient delivery systems. Here we report the development of a class of structurally versatile cationic lipopolyamines designed specifically for delivery of siRNA which show high levels of target transcript knockdown in a range of cell types in vitro. A primary benefit of these lipids is the ease with which they may be covalently modified by the addition of functional molecules. For in vivo applications one of the core lipids (Staramine) was modified with methoxypolyethylene glycols (mPEGs) of varying lengths. Upon systemic administration, PEGylated Staramine nanoparticles containing siRNA targeting the caveolin-1 (Cav-1) transcript caused a reduction of the Cav-1 transcript of up to 60%, depending on the mPEG length, specifically in lung tissue after 48h compared to treatment with non-silencing siRNA. In addition, modification with mPEG reduced toxicity associated with intravenous administration. The ability to produce a high level of target gene knockdown in the lung with minimal toxicity demonstrates the potential of these lipopolyamines for use in developing RNAi therapeutics for pulmonary disease.
Asunto(s)
Técnicas de Transferencia de Gen , Lípidos/administración & dosificación , Poliaminas/administración & dosificación , ARN Interferente Pequeño/genética , Animales , Caveolina 1/genética , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , L-Lactato Deshidrogenasa/metabolismo , Lípidos/síntesis química , Ratones , Nanopartículas/administración & dosificación , Nanopartículas/química , Poliaminas/síntesis química , Polietilenglicoles/administración & dosificación , Polietilenglicoles/químicaRESUMEN
BACKGROUND: The poor prognosis associated with ovarian cancer is primarily the result of delayed diagnosis and the lack of an effective treatment for advanced disease. Use of novel immunotherapy strategies are being evaluated that work to enhance local and systemic immune responses against cancer cells and can possibly work together with traditional cytotoxic chemotherapy regimens to produce more effective treatment options. METHODS: In the present study, we describe a gene-based therapy whereby the anticancer cytokine interleukin-12 gene (pmIL-12) is formulated with a synthetic polymeric delivery vehicle (PPC) and administered intraperitoneally into a mouse model of disseminated ovarian cancer. RESULTS: The administration of pmIL-12/PPC in tumor-bearing mice was associated with a shift towards a Th1 immune state, including significant increases in murine IL-12 (mIL-12) and interferon (IFN)-gamma (mIFN-gamma) in ascites fluid, with little change in systemic levels of these proteins. The mIL-12 protein was detectable for several days and could be reintroduced with subsequent injections. We show that treatment delayed the onset of ascites formation and improved survival in a dose-dependent manner. A significant decrease in vascular endothelial growth factor was associated with pmIL-12/PPC delivery and believed to play a predominant role in inhibiting ascites accumulation. Administration of pmIL-12/PPC was associated with minimal toxicity and, when combined with standard chemotherapies, resulted in additive improvement in survival. CONCLUSIONS: Taken together, these results suggest that pmIL-12/PPC may be an effective strategy for inhibiting progression of disseminated ovarian cancer and may offer a new option for treatment of advanced disease that can be used to complement standard therapies.
Asunto(s)
Terapia Genética , Interleucina-12/genética , Interleucina-12/uso terapéutico , Neoplasias Ováricas/genética , Neoplasias Ováricas/terapia , Animales , Ascitis/metabolismo , Recuento de Células Sanguíneas , Peso Corporal/efectos de los fármacos , Carboplatino/farmacología , Carboplatino/uso terapéutico , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Inyecciones Intraperitoneales , Interleucina-12/administración & dosificación , Interleucina-12/metabolismo , Ratones , Ratones Endogámicos C57BL , Proteínas de Neoplasias/sangre , Neoplasias Ováricas/sangre , Neoplasias Ováricas/tratamiento farmacológico , Paclitaxel/farmacología , Paclitaxel/uso terapéutico , ARN Mensajero/genética , ARN Mensajero/metabolismo , Análisis de Supervivencia , Carga Tumoral/efectos de los fármacos , VirusRESUMEN
The importance of DNA formulation in safe and efficient electrogene transfer is increasingly recognized as electroporation technology enters into clinical development. A phenomenal increase in naked DNA delivery by electroporation offers new opportunities for nonviral gene therapies previously considered difficult because of insufficient delivery. However, significant tissue damage related to harsh electroporation conditions raises serious safety concerns with the use of electroporation in healthy tissues, which limits its current applications to only nonhealthy tissues such as tumors. DNA formulations designed to minimize tissue damage or enhance expression at weaker electric pulses have been examined to address these concerns. These include formulations fortified with the addition of transfection reagent(s), membrane-permeating agents, tissue matrix modifiers, targeted ligands, or agents modifying electrical conductivity or membrane stability to enhance delivery efficiency or reduce tissue damage. These advancements in DNA formulation could prove to be useful in improving the safety of electroporation protocols for human applications.
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ADN Recombinante/administración & dosificación , Electroquimioterapia/métodos , Animales , ADN Recombinante/genética , Composición de Medicamentos , Electroporación/métodos , Terapia Genética/métodos , Oro , Humanos , Hialuronoglucosaminidasa , Liposomas , Nanopartículas del Metal , Polímeros , Cloruro de SodioRESUMEN
Interleukin-12 (IL-12) triggers an antitumoral immune response and an antiangiogenic effect against cancer. In this study, we tested a novel polymeric vehicle for IL-12 gene therapy along with adjuvant local biodegradable carmustine (BCNU) chemotherapy for the treatment of malignant glioma. Highly concentrated DNA/PPC (polyethylenimine covalently modified with methoxypolyethyleneglycol and cholesterol) complexes were used to deliver a murine plasmid encoding IL-12 (pmIL-12). For toxicity assessment, mice received intracranial injections with different volumes of pmIL-12/PPC. For efficacy, mice with intracranial GL261 glioma were treated with local delivery of pmIL-12/PPC and/or BCNU-containing polymers. Intracranial injections of 5-10 microl of pmIL-12/PPC were well tolerated and led to IL-12 expression in the brains of treated animals. Treatment with pmIL-12/PPC led to a significant increase in survival compared with untreated mice (median survival 57 days; 25% long-term survival >95 vs. 45 days for control; P<0.05). Treatment with BCNU led to a significant increase in survival compared with untreated mice, with 75% of treated mice having a long-term survival >95 days, (P<0.05). Most importantly, the combination of BCNU and pmIL-12/PPC led to a survival of 100% of the mice for 95 days after treatment (P<0.0001). This novel strategy is safe and effective for the treatment of malignant glioma. The synergy resultant from the combination of locally administered pmIL-12/PPC and BCNU suggests a role for this approach in the treatment of malignant brain tumors.
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Terapia Genética/métodos , Glioma/terapia , Interleucina-12/genética , Polímeros/química , Animales , Linfocitos T CD4-Positivos/patología , Linfocitos T CD8-positivos/patología , Células COS , Chlorocebus aethiops , Colesterol/química , Modelos Animales de Enfermedad , Sistemas de Liberación de Medicamentos/métodos , Terapia Genética/tendencias , Glioma/genética , Glioma/patología , Inyecciones , Interleucina-12/metabolismo , Estimación de Kaplan-Meier , Masculino , Ratones , Ratones Endogámicos C57BL , Plásmidos/administración & dosificación , Plásmidos/química , Plásmidos/genética , Polietilenglicoles/química , Transfección , Transgenes/genéticaRESUMEN
The synthesis and gene delivery application of a novel lipopolymer, PEG-PEI-CHOL (PPC), is described. PPC is composed of a low molecular weight branched polyethylenimine (PEI) covalently linked with functional groups methoxypolyethyleneglycol (PEG) and cholesterol (CHOL). The potential utility of PPC as a gene delivery polymer was evaluated by showing its ability to form stable nanocomplexes with DNA, protect DNA from degradation by DNase and mediate gene transfer in vitro and in vivo in solid tumors. The ratio of PEG/PEI/CHOL and nitrogen to phosphate (Polymer/DNA) was optimized for physico-chemical properties and gene delivery efficiency of PPC/DNA complexes. The gene therapy application of the polymer was shown following administration of a murine IL-12 plasmid (pmIL-12) formulated with PPC into tumors in mice which resulted in significant inhibition of tumor growth. The inhibitory effects of pmIL-12/PPC were enhanced when combined with specific chemotherapeutic agents, demonstrating the potential usefulness of pIL-12/PPC as an adjuvant therapy for cancer treatment.
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Terapia Genética/métodos , Inmunoterapia/métodos , Neoplasias/terapia , Animales , Antineoplásicos/uso terapéutico , Línea Celular Tumoral , Fenómenos Químicos , Química Física , Colesterol/química , Terapia Combinada , ADN/administración & dosificación , ADN/uso terapéutico , Femenino , Técnicas de Transferencia de Gen , Interleucina-2/genética , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C3H , Neoplasias/tratamiento farmacológico , Ensayos de Protección de Nucleasas , Plásmidos/genética , Polietilenglicoles/química , Polietileneimina/química , TransfecciónRESUMEN
Considerable progress in polymeric gene delivery systems has been made over the last several years. First generation polymers have been replaced by safer and more efficient carrier systems through molecular functionalization, improving polymer biocompatibility, biological stability, cell-specificity, and intracellular trafficking. Many new polymers have moved from in vitro characterization to preclinical validation in animal models of cancer, diabetes, and cardiovascular disorders. Although the transfection efficiency of most polymeric carriers is still significantly lower than that of viral vectors, their structural flexibility allows for continued improvement in polymer activity. Also, simple manufacturing and scale-up schemes and the low cost of manufacturing are likely to eventually compensate for the performance gap between viral and polymeric vectors and establish clinical recognition and commercialization of polymer-based gene therapy drugs.