Study Of Novel Nanomedicines Using Amphiphilic Drugs As Excipients

Chemotherapy is still indispensable for cancer treatments.However,most anticancer drugsare hydrophobic with rapid blood clearance,which result in low therapeutic efficacy and severeside effects.Nanomedicines possess therapeutic advantages over free drugs,including enhancedwater solubility,prolonged circulation time,and accumulated tumor drug concentration.Large majority of these reported nanomedicines,however,failed to enter clinical translation.On the one hand,these nanomedicines use carrier materials that have not been approved asexcipients by FDA or CFDA;their ADME and systemic and long-term toxicities are unknown,which will need huge efforts to obtain these data for approval as drug excipients.On the otherhand,the designs and preparation processes are too complexed to establish effective GMPprocesses for clinical translation.While most clinical anticancer drugs are hydrophobic,many ofthem are amphiphilic.For example,irinotecan hydrochloride has a hydrophilic piperidine headand a camptothecin hydrophobic tail.We thereby have proposed to use amphiphilic drugs asemulsifiers to disperse hydrophobic drugs and assemble into nanoparticles.This will avoid theusage of exotic materials and make the resulting nanomedine readily translational.Along this line,the first part of this thesis is using this strategy to prepare a7-ethyl-10-hydroxyl-camptothecin(SN38)nanoformulation.CPT11 self-assembles with itsinsoluble active parent drug,SN38,into stable and water-dispersible nanoparticles,increasingSN38's water solubility by thousands of times up to 25 mg/mL with a loading efficiency close to100%.These nanodispersions have much increased bioavailability and thereby improvedanti-cancer activities.In vivo and in vitro studies show that SN38/CPT11 nanoparticlespossesses superior antitumor efficacy over free CPT11 at the equivalent dose.Chapter 3 is to optimize CPT11/SN38 nanoformulation for clinical translation.SN38 isincompatible with current excipients including polymers and liposomes and thus has not beenencapsulated into any systems.By adding a small amount of CPT11 to disturb the crystallizationof SN38,stable SN38 nanodispersions are easily formed with tocopheryl polyethylene glycol1000 succinate(TPGS).The formulations cover positive charges of CPT11/SN38 NPs withimprove bioavailability,pharmacokinetics and antitumor activity in vivo.In addition,takingadvantage of the reversible formation of the e-lactone form in acid and opening as carboxylic salt in base of SN38,an organic solvent-free alkaline/acid method is developed to fabricateSN38/CPT11 nanoformulation,which avoids any organic solvent addition to the formulation.Chapter 4 is on the developments of curcumin formulations using this technology.Curcumin is well-known as a potent antioxidant,free radical scavenger and anti-inflammatoryagent as well as anti-carcinogenic properties.However,its low water solubility andbioavailability limit its applications.Indocyanine green(ICG)and amphiphilic drugs CPT11/DOX HCl were used to solubilize curcumin,respectively.The cell toxicity and antitumorstudies showed a higher anticancer capacity and a lower side effect ofcurcumin/chemotherapeutics NPs than administration respectively.Chapter 5 is to develop nanomedicines for the combinational therapy.ICG is amphiphilicwith two hydrophilic sulfonic acid groups and a hydrophobic benzene ring structure.ICG isfound to solubilize many hydrophobic drugs into NPs or solutions,including PTX and curcumin.With the addition of hydrophobic drug molecules,the self-quenching of ICG in thenanoformulations is also prohibited and thus its fluorescence and photosensitivity are promoted.Particularly,ICG/SN38 NPs deliver the hydrophobic drug and have an enhanced thephotodynamic and photothermal therapy efficiency at the same time.The combined treatmentresults in tumors eradication without recurrence,while the chemotherapy with the same dose ofSN38 or the photodynamic treatment alone can only reduce the tumor sizes.The last part is to develop a rhodamine isothiocyanate(RBITC)-based tumor early detectiontechnology.RBITC is found to be quenched in healthy organs,while highly fluorescent in solidand metastatic tumors.Hemoglobin cause the quench of RBITC,fluorescence would show up inhemolysis model induced by injection of phenylhydrazine;on the other hand,RBITC would bede-quenched in acute liver injury model induced by NaAsO2,as well as in metastatic tumormodels,and the intensity of fluorescence directly proportional to the deterioration of cancer,which suggests that the dye could be used to detect the early damage of organs.