Biomaterial-Based Sustained-Release Drug Formulations for Localized Cancer Immunotherapy.

Cancer immunotherapy has revolutionized clinical cancer treatments by taking advantage of the immune system to selectively and effectively target and kill cancer cells. However, clinical cancer immunotherapy treatments often have limited efficacy and/or present severe adverse effects associated primarily with their systemic administration. Localized immunotherapy has emerged to overcome these limitations by directly targeting accessible tumors via local administration, reducing potential systemic drug distribution that hampers drug efficacy and safety. Sustained-release formulations can prolong drug activity at target sites, which maximizes the benefits of localized immunotherapy to increase the therapeutic window using smaller dosages than those used for systemic injection, avoiding complications of frequent dosing. The performance of sustained-release formulations for localized cancer immunotherapy has been validated preclinically using various implantable and injectable scaffold platforms. This review introduces the sustained-release formulations developed for localized cancer immunotherapy and highlights their biomaterial-based platforms for representative classes, including inorganic scaffolds, natural hydrogels, synthetic hydrogels, and microneedle patches. The design rationale and other considerations are summarized for further development of biomaterials for the construction of optimal sustained-release formulations.

Oral lymphatic delivery of alpha-galactosylceramide and ovalbumin evokes anti-cancer immunization.

We developed an orally delivered nanoemulsion that induces cancer immunization. It consists of tumor antigen-loaded nano-vesicles carrying the potent invariant natural killer T-cell (iNKT) activator α-galactosylceramide (α-GalCer), to trigger cancer immunity by effectively activating both innate and adaptive immunity. It was validated that adding bile salts to the system boosted intestinal lymphatic transport as well as the oral bioavailability of ovalbumin (OVA) via the chylomicron pathway. To increase intestinal permeability further and amplify the antitumor responses, an ionic complex of cationic lipid 1,2-dioleyl-3-trimethylammonium propane (DTP) with sodium deoxycholate (DA) (DDP) and α-GalCer were anchored onto the outer oil layer to form OVA-NE#3. As expected, OVA-NE#3 exhibited tremendously improved intestinal cell permeability as well as enhanced delivery to mesenteric lymph nodes (MLNs). Subsequent activation of dendritic cells and iNKTs, in MLNs were also observed. Tumor growth in OVA-expressing mice with melanoma was more strongly suppressed (by 71%) after oral administration of OVA-NE#3 than in untreated controls, confirming the strong immune response induced by the system. The serum levels of OVA-specific IgG1 and IgG2a were 3.52- and 6.14-fold higher than in controls. Treating OVA-NE#3 increased the numbers of tumor-infiltrating lymphocytes, including cytotoxic T-cell and M1-like macrophage. Antigen- and α-GalCer-associated enrichment of dendritic cells and iNKTs in tumor tissues also increased after OVA-NE#3 treatment. These observations indicate that our system induces both cellular and humoral immunity by targeting the oral lymphatic system. It may offer a promising oral anti-cancer vaccination strategy that involves the induction of systemic anti-cancer immunization.

Studies to Elucidate the Mechanism of Cardio Protective and Hypotensive Activities of Anogeissus acuminata (Roxb. ex DC.) in Rodents.

Anogeissus acuminata (Roxb. ex DC.) is a folkloric medicinal plant in Asia; including Pakistan; used as a traditional remedy for cardiovascular disorders. This study was planned to establish a pharmacological basis for the trivial uses of Anogeissus acuminata in certain medical conditions related to cardiovascular systems and to explore the underlying mechanisms. Mechanistic studies suggested that crude extract of Anogeissus acuminata (Aa.Cr) produced in vitro cardio-relaxant and vasorelaxant effects in isolated paired atria and aorta coupled with in vivo decrease in blood pressure by invasive method; using pressure and force transducers connected to Power Lab Data Acquisition System. Moreover; Aa.Cr showed positive effects in left ventricular hypertrophy in Sprague Dawley rats observed hemodynamically by a decrease in cardiac cell size and fibrosis; along with absence of inflammatory cells; coupled with reduced levels of angiotensin converting enzyme (ACE) and renin concentration along with increased concentrations of nitric oxide (NO) and cyclic guanosine monophosphate (cGMP). In Acute Myocardial Infarction (AMI) model; creatine kinase (CK), creatine kinase-MB (CK-MB) and lactic acid dehydrogenase (LDH levels) were found to be decreased; along with decreased necrosis; edema and recruitment of inflammatory cells histologically. In vivo and ex vivo studies of Anogeissus acuminata provided evidence of vasorelaxant; hypotensive and cardioprotective properties facilitated through blockage of voltage-gated Ca++ ion channel; validating its use in cardiovascular diseases.

Ex vivo and in vivo studies of Viola tricolor Linn. as potential cardio protective and hypotensive agent: Inhibition of voltage-gated Ca++ ion channels.

Viola tricolor Linn. is used as cardio-protective and anti-hypertensive agent in traditional medicine. Current study objective was to evaluate cardio-protective and hypotensive effects of Viola tricolor L. in vitro and in vivo studies. Viola tricolor L. crude extract (Vt.Cr) and its fractions (Aqueous and organic) were tested at rabbit atria and aorta coupled to Power Lab Data Acquisition System for cardio depressant and vasorelaxant effects in vitro whereas in vivo Blood Pressure was checked by invasive method in normotensive ketamine-diazepam anesthetized rats. Isoproterenol was employed for acute myocardial infarction (AMI) and left ventricular hypertrophy (LVH) development and cardioprotective effects of Vt.Cr were evaluated hemodynamically and histopathologically. Vt.Cr and its fractions decreased heart rate and contractile force in paired atria and relaxed Phenylephrine (1 µM) and K+ (80 mM) stimulated contractions in aorta possibly mediated through Voltage dependent L-type calcium channels blockage supported by in vivo hypotensive action. In LVH, Vt.Cr lowered Angiotensin Converting Enzymes and renin, increased cyclic Guanosine Monophosphate and nitric oxide levels, decreased cardiomyocytes size and fibrosis attributed to Gallic acid as detected by High Performance Liquid Chromatography. Partial positive results were seen hemodynamically and histologically in AMI Viola tricolor L. showed vasorelaxant, cardio-relaxant, hypotensive, and cardio protective effect validating traditional practice in cardiovascular disorders.